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Wang F, Chen G, Zhang Z, Yuan Y, Wang Y, Gao Y, Sheng W, Wang Z, Li X, Yuan X, Cai S, Ren L, Liu Y, Xu J, Zhang Y, Liang H, Wang X, Zhou A, Ying J, Li G, Cai M, Ji G, Li T, Wang J, Hu H, Nan K, Wang L, Zhang S, Li J, Xu R. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of colorectal cancer, 2024 update. Cancer Commun (Lond) 2025; 45:332-379. [PMID: 39739441 PMCID: PMC11947620 DOI: 10.1002/cac2.12639] [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: 11/27/2024] [Accepted: 12/02/2024] [Indexed: 01/02/2025] Open
Abstract
The 2024 updates of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for the diagnosis and treatment of colorectal cancer emphasize standardizing cancer treatment in China, highlighting the latest advancements in evidence-based medicine, healthcare resource access, and precision medicine in oncology. These updates address disparities in epidemiological trends, clinicopathological characteristics, tumor biology, treatment approaches, and drug selection for colorectal cancer patients across diverse regions and backgrounds. Key revisions include adjustments to evidence levels for intensive treatment strategies, updates to regimens for deficient mismatch repair (dMMR)/ microsatellite instability-high (MSI-H) patients, proficient mismatch repair (pMMR)/ microsatellite stability (MSS) patients who have failed standard therapies, and rectal cancer patients with low recurrence risk. Additionally, recommendations for digital rectal examination and DNA polymerase epsilon (POLE)/ DNA polymerase delta 1 (POLD1) gene mutation testing have been strengthened. The 2024 CSCO Guidelines are based on both Chinese and international clinical research, as well as expert consensus, ensuring their relevance and applicability in clinical practice, while maintaining a commitment to scientific rigor, impartiality, and timely updates.
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Affiliation(s)
- Feng Wang
- Department of Medical OncologySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
| | - Gong Chen
- Department of Colorectal SurgerySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerGuangzhouGuangdongP. R. China
| | - Zhen Zhang
- Department of Radiation OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Ying Yuan
- Department of Medical OncologyThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Yi Wang
- Department of RadiologyPeking University People's HospitalBeijingP. R. China
| | - Yuan‐Hong Gao
- Department of Radiation OncologySun Yat‐sen University Cancer Centre, The State Key Laboratory of Oncology in South ChinaGuangzhouGuangdongP. R. China
| | - Weiqi Sheng
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Zixian Wang
- Department of Medical OncologySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
| | - Xinxiang Li
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Xianglin Yuan
- Department of OncologyTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Sanjun Cai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Li Ren
- Department of General SurgeryZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Yunpeng Liu
- Department of Medical OncologyThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Jianmin Xu
- Department of General SurgeryZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Yanqiao Zhang
- Department of OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiangP. R. China
| | - Houjie Liang
- Department of OncologySouthwest HospitalThird Military Medical University (Army Medical University)ChongqingP. R. China
| | - Xicheng Wang
- Department of Gastrointestinal OncologyCancer Medical Center, Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina
| | - Aiping Zhou
- Department of Medical OncologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jianming Ying
- Department of PathologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Guichao Li
- Department of Radiation OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Muyan Cai
- Department of PathologySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South ChinaGuangzhouGuangdongP. R. China
| | - Gang Ji
- Department of Gastrointestinal SurgeryXijing HospitalAir Force Military Medical UniversityXi'anShaanxiP. R. China
| | - Taiyuan Li
- Department of General SurgeryThe First Affiliated Hospital of Nanchang UniversityNanchangJiangxiP. R. China
| | - Jingyu Wang
- Department of RadiologyThe First Hospital of Jilin UniversityChangchunJilinP. R. China
| | - Hanguang Hu
- Department of Medical OncologyThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Kejun Nan
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiP. R. China
| | - Liuhong Wang
- Department of RadiologySecond Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Suzhan Zhang
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Jin Li
- Department of Medical OncologyShanghai GoBroad Cancer HospitalChina Pharmaceutical UniversityShanghaiP. R. China
| | - Rui‐Hua Xu
- Department of Medical OncologySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat‐sen University, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
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Wongkraisri C, Chusuwanrak K, Laocharoenkeat A, Chularojanamontri L, Nimmannit A, Ithimakin S. Randomized controlled trial on the efficacy of topical urea-based cream in preventing capecitabine-associated hand-foot syndrome. BMC Cancer 2025; 25:275. [PMID: 39962445 PMCID: PMC11831840 DOI: 10.1186/s12885-025-13684-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 02/07/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Hand-foot syndrome (HFS) is a common adverse event of capecitabine causing treatment modifications. Topical urea cream can reduce sorafenib-induced hand-foot skin reaction. However, its benefit in preventing capecitabine-associated HFS was not seen early in the course and had been unknown with long-term use. The aim of this study was to evaluate the efficacy of urea cream for HFS prophylaxis throughout capecitabine treatment. METHODS Patients with cancer who received capecitabine were randomized (1:1) to receive usual care alone or in combination with urea-based cream. The incidence and degree of HFS were assessed at each capecitabine cycle. The primary endpoint was the proportion of patients with any grade HFS. The secondary endpoints included the proportion of patients with severe (≥ grade 3) HFS, modifications in capecitabine because of HFS, and HFS onset. RESULTS After a median of six capecitabine cycles, any grade HFS was reported by 68 of 109 patients (62.4%) who received usual care and by 60 of 107 patients (56%) who used urea cream (p = 0.36). The patients who received usual care and urea cream had similar proportions of grade 3 HFS occurrence [52 (47.7%) vs. 44 (41.1%), respectively, p = 0.34] and needed capecitabine modification because of HFS [20 patients (18.3%) vs. 17 patients (15.9%), respectively, p = 0.89], as well as similar HFS onset. CONCLUSIONS Urea-based cream did not prevent capecitabine-associated HFS, reduce capecitabine modification, and delay HFS onset. However, it had a tendency to lessen HFS severity, especially in the later cycles of capecitabine. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT05348278, registered on April 21, 2022.
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Affiliation(s)
- Concord Wongkraisri
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kriengkrai Chusuwanrak
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - Leena Chularojanamontri
- Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Akarin Nimmannit
- Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Suthinee Ithimakin
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Hughes H, Jajodia A, Soyer P, Mellnick V, Patlas MN. Bowel Emergencies in Patients With Cancer. Can Assoc Radiol J 2025; 76:76-86. [PMID: 38721789 DOI: 10.1177/08465371241252035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2024] Open
Abstract
Cancer is the second most common cause of death worldwide. Bowel emergencies in patients with cancer are becoming increasingly more prevalent due to advances in cancer therapy and longer overall patient survival. When these patients present acutely, they are often frail and may have pre-existing co-morbidities. This article discusses the imaging features of bowel emergencies commonly encountered in oncological patients in clinical practice. These include chemotherapy related colitis, neutropenia enterocolitis and typhlitis, toxic megacolon, bowel perforation, malignant bowel obstruction and gastrointestinal haemorrhage. The radiologist plays a key role in identifying these oncological emergencies and guiding further management.
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Affiliation(s)
- Hannah Hughes
- Department of Radiology, St. Vincent's University Hospital, Dublin, Ireland
| | - Ankush Jajodia
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
| | - Philippe Soyer
- Department of Radiology, Hôpital Cochin, Assistance Publique-Hopitaux de Paris, Paris, France
- Faculté de Médecine, Université Paris Cité, Paris, France
| | - Vincent Mellnick
- Department of Radiology, Mallinckrodt Institute of Radiology, St Louis, MO, USA
| | - Michael N Patlas
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
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Keshavarzi F, Salari N, Jambarsang S, Mohammad Tabatabaei S, Shahsavari S, Fournier AJ. Overall survival with non-proportional hazards in first-line treatment for patients with metastatic colorectal cancer: Systematic review and network meta-analysis. Heliyon 2024; 10:e36464. [PMID: 39253267 PMCID: PMC11381762 DOI: 10.1016/j.heliyon.2024.e36464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 08/15/2024] [Accepted: 08/15/2024] [Indexed: 09/11/2024] Open
Abstract
This study aimed to identify the most effective first-line treatment for patients with metastatic colorectal cancer based on overall survival, identify the most commonly used treatment, and generate a meaningful ranking among all available treatments based on their relative effectiveness. Researchers used the ANOVA parametrization method to fit the second-order fractional polynomial network meta-analysis with a random-effect model. Using a non-proportional hazards network meta-analysis, 46 treatments were compared by considering a combination of direct and indirect evidence extracted from clinical trial studies. Included in the review were 46 trials involving 21350 patients. Between January 2000 and January 2023, researchers conducted a thorough search through Embase, PubMed/Medline, and Scopus. To undertake a secondary analysis of this data, we recreate individual patient data from published Kaplan-Meier (K-M) survival curves and assess the accuracy of that reconstruction. A random-effects model was used to evaluate the pooled overall survival and hazard ratio with a 95 percent confidence interval. The predicted survival curves for the network meta-analysis showed that GOLFIG and FOLFOX + Cetuximab treatments have higher survival, respectively. Our results provide moderate quality evidence and comparative effective estimates for various available first-line treatments for metastasis colorectal cancer based on network meta-analysis.
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Affiliation(s)
- Fatemeh Keshavarzi
- Department of Biostatistics, Faculty of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nader Salari
- Department of Biostatistics, Faculty of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sara Jambarsang
- Department of Bio-Statistics and Epidemiology, Shahid Sadoughi University of Medical Science, Yazd, Iran
| | - Seyyed Mohammad Tabatabaei
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodeh Shahsavari
- Department of Health Information Management, School of Allied Medical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Cohen R, Raeisi M, Chibaudel B, Shi Q, Yoshino T, Zalcberg JR, Adams R, Cremolini C, Van Cutsem E, Heinemann V, Tabernero J, Punt CJA, Arnold D, Hurwitz HI, Douillard JY, Venook AP, Saltz LB, Maughan TS, Kabbinavar F, Bokemeyer C, Grothey A, Mayer RJ, Kaplan R, Tebbutt NC, Randolph Hecht J, Giantonio BJ, Díaz-Rubio E, Sobrero AF, Peeters M, Koopman M, Goldberg RM, Andre T, de Gramont A. Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis. Eur J Cancer 2024; 207:114160. [PMID: 38896997 DOI: 10.1016/j.ejca.2024.114160] [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: 04/20/2024] [Revised: 05/27/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.
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Affiliation(s)
- Romain Cohen
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France
| | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Levallois-Perret, France
| | - Qian Shi
- Department of Quantitative Health Science, Mayo Clinic, Rochester, USA
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - John R Zalcberg
- Monash University School of Public Health and Preventive Medicine and Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia
| | - Richard Adams
- Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom
| | - Chiara Cremolini
- Department of Translational Research and New Technologies, University of Pisa, Pisa, Italy
| | - Eric Van Cutsem
- Department of Gastrointestinal and Liver Diseases, Digestive Oncology Unit, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Volker Heinemann
- Department of Medical Oncology, LMU Hospital, University of Munich, Munich, Germany
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, Asklepios Klinik Altona, Hamburg, Germany
| | | | - Jean-Yves Douillard
- Medical Oncology Department, Integrated Centers for Oncology Nantes, Nantes, France
| | - Alan P Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA, USA
| | | | | | | | - Carsten Bokemeyer
- Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Niall C Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer, Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - J Randolph Hecht
- David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, USA
| | | | | | | | | | - Miriam Koopman
- University Medical Center Utrecht, Utrecht, the Netherlands
| | - Richard M Goldberg
- Department of Medicine, West Virginia University Cancer Institute, Morgantown, USA
| | - Thierry Andre
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France; ARCAD Foundation, Paris, France
| | - Aimery de Gramont
- ARCAD Foundation, Paris, France; Department of Medical Oncology, Franco-British Hospital, Levallois-Perret, France
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Zhan Y, Cheng X, Mei P, Tan S, Feng W, Jiang H. Safety of first-line systemic therapy in patients with metastatic colorectal cancer: a network meta-analysis of randomized controlled trials. BMC Cancer 2024; 24:893. [PMID: 39048944 PMCID: PMC11270896 DOI: 10.1186/s12885-024-12662-3] [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: 11/09/2023] [Accepted: 07/19/2024] [Indexed: 07/27/2024] Open
Abstract
OBJECTIVE To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis. METHODS The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens. RESULTS A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs. CONCLUSION In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.
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Affiliation(s)
- Yanrong Zhan
- Rudong People's Hospital / Affiliated Rudong Hospital of Xinglin College, Nantong University, Nantong, Jiangsu, 226400, China.
| | - Xianwen Cheng
- Ankang Hospital of Traditional Chinese Medicine, Ankang, Shaanxi, 725000, China
| | - Pingping Mei
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shufa Tan
- Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China
| | - Wenzhe Feng
- Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China.
| | - Hua Jiang
- Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China
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Rais T, Riaz R, Siddiqui T, Shakeel A, Khan A, Zafar H. Innovations in colorectal cancer treatment: trifluridine and tipiracil with bevacizumab for improved outcomes - a review. Front Oncol 2024; 14:1296765. [PMID: 39070141 PMCID: PMC11272516 DOI: 10.3389/fonc.2024.1296765] [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: 10/06/2023] [Accepted: 06/14/2024] [Indexed: 07/30/2024] Open
Abstract
Colorectal cancer ranks second in cancer-related deaths throughout the world. At the time of diagnosis, at least 20% of the patients with CRC had already developed metastases. Treating and effectively managing metastatic colorectal cancer remains an unsolved task for the health sector. Research and clinical trials have been done to find the best possible solution for patients diagnosed with metastatic colorectal cancer. The approval of the combination therapy of trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer (CRC) by the Food and Drug Administration (FDA) is a remarkable breakthrough in CRC treatment. Our goal through this article is to give detailed knowledge about the pathogenesis of CRC, its prevalence, and its clinical features. Here, we have also discussed the past medical treatments that have been used for treating mCRC, including the anti-EGFR therapy, aflibercept, ramucirumab, and regorafenib. However, the focus of this document is to assess the combination of LONSURF (trifluridine/tipiracil) and bevacizumab by reviewing the clinical trials and relevant research.
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Affiliation(s)
- Taruba Rais
- Internal Medicine, Dow University of Health Sciences (DUHS), Karachi, Pakistan
| | - Rumaisa Riaz
- Internal Medicine, Dow University of Health Sciences (DUHS), Karachi, Pakistan
| | - Tasmiyah Siddiqui
- Internal Medicine, Dow University of Health Sciences (DUHS), Karachi, Pakistan
| | - Amna Shakeel
- Internal Medicine, Dow University of Health Sciences (DUHS), Karachi, Pakistan
| | - Afsheen Khan
- Internal Medicine, Dow University of Health Sciences (DUHS), Karachi, Pakistan
| | - Habiba Zafar
- Internal Medicine, Jinnah Sindh Medical University (JSMU), Karachi, Pakistan
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Takada T, Katoh R, Yamada K, Ojima H. Two cases of metastatic colorectal cancer with prolonged liver injury following capecitabine combination chemotherapy. BMJ Case Rep 2024; 17:e260012. [PMID: 38969391 DOI: 10.1136/bcr-2024-260012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2024] Open
Abstract
We present two cases of metastatic colorectal cancer where a liver injury developed while receiving capecitabine. In both cases, the patients were switched from oral capecitabine to a continuous intravenous 5-fluorouracil infusion and were able to continue treatment without a relapse of hepatotoxicity.
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Affiliation(s)
- Takahiro Takada
- Gastrointestinal Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma, Japan
| | - Ryuji Katoh
- Gastrointestinal Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma, Japan
| | - Kazunosuke Yamada
- Gastrointestinal Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma, Japan
| | - Hitoshi Ojima
- Gastrointestinal Surgery, Gunma Prefectural Cancer Center, Ohta, Gunma, Japan
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Santhosh A, Sharma A, Bakhshi S, Kumar A, Sharma V, Malik PS, Pramanik R, Gogia A, Prasad CP, Sehgal T, Gund S, Dev A, Cheung WY, Pandey RM, Kumar S, Gupta I, Batra A. Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial. J Clin Oncol 2024; 42:1821-1829. [PMID: 38412399 DOI: 10.1200/jco.23.01730] [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: 08/10/2023] [Revised: 12/06/2023] [Accepted: 12/20/2023] [Indexed: 02/29/2024] Open
Abstract
PURPOSE Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS. METHODS In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression. RESULTS In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4). CONCLUSION Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.
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Affiliation(s)
- Akhil Santhosh
- Department of Medical Oncology, BRAIRCH, AIIMS, Delhi, India
| | - Atul Sharma
- Department of Medical Oncology, BRAIRCH, AIIMS, Delhi, India
| | - Sameer Bakhshi
- Department of Medical Oncology, BRAIRCH, AIIMS, Delhi, India
| | - Akash Kumar
- Department of Medical Oncology, National Cancer Institute Jhajjar, AIIMS, New Delhi, India
| | - Vinod Sharma
- Department of Medical Oncology, National Cancer Institute Jhajjar, AIIMS, New Delhi, India
| | | | - Raja Pramanik
- Department of Medical Oncology, BRAIRCH, AIIMS, Delhi, India
| | - Ajay Gogia
- Department of Medical Oncology, BRAIRCH, AIIMS, Delhi, India
| | | | - Tushar Sehgal
- Department of Laboratory Medicine, AIIMS, Delhi, India
| | - Sneha Gund
- Department of Medical Oncology, BRAIRCH, AIIMS, Delhi, India
| | - Arundhathi Dev
- Department of Medical Oncology (LAB), BRAIRCH, AIIMS, Delhi, India
| | - Winson Y Cheung
- Department of Medical Oncology, Tom Baker Cancer Centre Calgary, Calgary, Canada
| | - R M Pandey
- Department of Biostatistics, AIIMS, Delhi, India
| | - Saran Kumar
- Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, India
| | - Ishaan Gupta
- Department of Biomedical Engineering and Biotechnology, Indian Institute of Technology, Delhi, India
| | - Atul Batra
- Department of Medical Oncology, BRAIRCH, AIIMS, Delhi, India
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10
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Legoux JL, Faroux R, Barrière N, Le Malicot K, Tougeron D, Lorgis V, Guerin-Meyer V, Bourgeois V, Malka D, Aparicio T, Baconnier M, Lebrun-Ly V, Egreteau J, Khemissa Akouz F, Terme M, Lepage C, Boige V. First-Line LV5FU2 with or without Aflibercept in Patients with Non-Resectable Metastatic Colorectal Cancer: A Randomized Phase II Trial (PRODIGE 25-FFCD-FOLFA). Cancers (Basel) 2024; 16:1515. [PMID: 38672597 PMCID: PMC11049283 DOI: 10.3390/cancers16081515] [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: 03/27/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Fluropyrimidine monotherapy is an option for some patients with inoperable metastatic colorectal cancer. Unlike bevacizumab, the addition of aflibercept, an antibody acting as an anti-angiogenic agent, has never been evaluated in this context. The aim of the study was to determine whether aflibercept could increase the efficacy of fluoropyrimidine monotherapy without increasing toxicity. This multicenter phase II non-comparative trial evaluated the addition of aflibercept to infusional 5-fluorouracil/folinic acid (LV5FU2 regimen) as first-line treatment in patients unfit to receive doublet cytotoxic chemotherapy. The primary endpoint was 6-month progression-free survival (PFS). The clinical hypotheses expected a PFS rate at 6 months of over 40% (60% expected). A total of 117 patients, with a median age of 81 years, were included: 59 in arm A (LV5FU2-aflibercept) and 58 in arm B (LV5FU2 alone). Six-month PFS was 54.7% in both arms (90% CI 42.5-66.5 in both). Median overall survival was 21.8 months (arm A) and 25.1 months (arm B). Overall toxicity was more common in arm A: grade ≥ 3 toxicity in 82% versus 58.2%. Given the 6-month PFS, the study can be considered positive. However, the toxicity of aflibercept in this population was high, and continuation of the trial into phase III is not envisaged.
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Affiliation(s)
- Jean-Louis Legoux
- Department of Hepato-Gastroenterology and Digestive Oncology, CHU d’Orléans, 14 avenue de l’Hôpital, CS 86709, 45067 Orleans CEDEX 2, France
| | - Roger Faroux
- Department of Hepato-Gastroenterology and Digestive Oncology, Centre Hospitalier Les Oudairies, Boulevard Stéphane Moreau, 85925 La Roche sur Yon, France;
| | - Nicolas Barrière
- Department of Hepato-Gastroenterology and Digestive Oncology, Hôpital Européen, 6 Rue Désirée Clary, CS 70356, 13331 Marseille CEDEX 03, France;
| | - Karine Le Malicot
- Fédération Francophone de Cancérologie Digestive (FFCD), EPICAD INSERM LNC-UMR 1231, Faculté de Médecine, University of Burgundy and Franche Comté, 7, Boulevard Jeanne d’Arc, 21079 Dijon, France;
| | - David Tougeron
- Department of Hepato-Gastroenterology, CHU de Poitiers, 2 Rue de la Miletrie, BP 577, 86021 Poitiers, France;
| | - Véronique Lorgis
- Department of Medical Oncology, Institut de Cancérologie de Bourgogne, GRReCC, 18 Cours Général de Gaulle, 21000 Dijon, France;
| | - Véronique Guerin-Meyer
- Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Boulevard Jacques Monod, 44805 Saint Herblain, France;
| | - Vincent Bourgeois
- Department of Hepato-Gastroenterology and Digestive Oncology, Centre Hospitalier Duchenne, Allée Jacques Monod-BP 609, 62321 Boulogne Sur Mer, France;
| | - David Malka
- Department of Cancer Medicine, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif CEDEX, France; (D.M.); (V.B.)
| | - Thomas Aparicio
- Department of Gastroenterology, Saint Louis Hospital, APHP, Université Paris Cité, Paris, 1 Avenue Claude Vellefaux, 75475 Paris, France;
| | - Matthieu Baconnier
- Department of Gastroenterology, Centre Hospitalier Annecy-Genevois, 1 Avenue de l’Hôpital, 74374 Pringy, France;
| | - Valérie Lebrun-Ly
- Department of Medical Oncology, CHU Dupuytren, 2 Avenue Martin Luther King, 87042 Limoges, France;
| | - Joëlle Egreteau
- Radiotherapy and Medical Oncology, Groupe Hospitalier Bretagne Sud, 5 Avenue de Choiseul, BP 12233, 56322 Lorient CEDEX, France;
| | - Faïza Khemissa Akouz
- Department of Hepato-Gastroenterology and Digestive Oncology, Saint Jean Hospital, 20 Avenue du Languedoc, BP 49954, 66046 Perpignan CEDEX 9, France;
| | - Magali Terme
- INSERM U970—PARCC (Paris Cardiovascular Research Center), European Georges Pompidou Hospital, Université Paris Descartes, Sorbonne Paris Cité, 56 rue Leblanc, 75015 Paris, France;
| | - Côme Lepage
- INSERM U866, Université de Bourgogne, 7 Boulevard Jeanne d’Arc, BP 27877, 21078 Dijon CEDEX, France;
| | - Valérie Boige
- Department of Cancer Medicine, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif CEDEX, France; (D.M.); (V.B.)
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11
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Colloca GA, Venturino A. Prognostic Effect of Performance Status on Outcomes of Patients with Colorectal Cancer Receiving First-Line Chemotherapy: A Meta-analysis. J Gastrointest Cancer 2024; 55:418-426. [PMID: 37966630 DOI: 10.1007/s12029-023-00983-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2023] [Indexed: 11/16/2023]
Abstract
BACKGROUND Performance status (PS) is a variable derived from the assessment of a patient's functional status, originally proposed to predict drug toxicity. However, despite its characteristic of being subjective and unidimensional, it has become one of the most important prognostic variables for patients with metastatic colorectal cancer (mCRC). In light of the considerable progressive prolongation of median overall survival (OS) of patients with mCRC, it is unclear whether PS continues to be a valid prognostic factor. This article aims to perform a meta-analysis to verify the current prognostic role of PS. METHODS A search on two databases of prospective trials of first-line chemotherapy in mCRC patients, published in English from 1991 to 2020, was done by predefined criteria. After the selection of phase III trials evaluating the prognostic role of PS, a meta-analysis has been performed. RESULTS Thirteen trials were included in the meta-analysis. They reported a reduction in the risk of death with a PS 0 compared to a PS 1 or more (HR 0.63, CI 0.54-0.72; 13 studies), which was confirmed for the comparison between PS 0 and PS 1. However, the study found significant heterogeneity (Q = 68.10; p-value < 0.001) and high-grade inconsistency (I2 = 82.38%). Therefore, to explore the reasons for the heterogeneity, a univariate meta-regression was performed, which suggested a possible moderating activity for liver metastases and timing of metastasis. CONCLUSIONS PS is a reliable prognostic factor for patients with mCRC receiving first-line chemotherapy but is poorly evaluated in phase III trials.
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Jacobsen A, Siebler J, Grützmann R, Stürzl M, Naschberger E. Blood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives. Cancers (Basel) 2024; 16:890. [PMID: 38473252 DOI: 10.3390/cancers16050890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/06/2024] [Accepted: 02/10/2024] [Indexed: 03/14/2024] Open
Abstract
The vasculature is a key player and regulatory component in the multicellular microenvironment of solid tumors and, consequently, a therapeutic target. In colorectal carcinoma (CRC), antiangiogenic treatment was approved almost 20 years ago, but there are still no valid predictors of response. In addition, treatment resistance has become a problem. Vascular heterogeneity and plasticity due to species-, organ-, and milieu-dependent phenotypic and functional differences of blood vascular cells reduced the hope of being able to apply a standard approach of antiangiogenic therapy to all patients. In addition, the pathological vasculature in CRC is characterized by heterogeneous perfusion, impaired barrier function, immunosuppressive endothelial cell anergy, and metabolic competition-induced microenvironmental stress. Only recently, angiocrine proteins have been identified that are specifically released from vascular cells and can regulate tumor initiation and progression in an autocrine and paracrine manner. In this review, we summarize the history and current strategies for applying antiangiogenic treatment and discuss the associated challenges and opportunities, including normalizing the tumor vasculature, modulating milieu-dependent vascular heterogeneity, and targeting functions of angiocrine proteins. These new strategies could open perspectives for future vascular-targeted and patient-tailored therapy selection in CRC.
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Affiliation(s)
- Anne Jacobsen
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of General and Visceral Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Jürgen Siebler
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of Medicine 1-Gastroenterology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Robert Grützmann
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of General and Visceral Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
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13
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Han G, Cui L, Sun C, Yu L, Liu S. Efficacy of mFOLFOX6 plus bevacizumab regimen in advanced colorectal cancer after deep hyperthermia: a single-center retrospective study. Front Oncol 2023; 13:1259713. [PMID: 38125935 PMCID: PMC10732353 DOI: 10.3389/fonc.2023.1259713] [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: 07/16/2023] [Accepted: 11/22/2023] [Indexed: 12/23/2023] Open
Abstract
Background This study aimed to explore the clinical efficacy and safety of a modified FOLFOX6 (oxaliplatin + leucovorin + 5-fluorouracil) plus bevacizumab regimen after deep hyperthermia in advanced colorectal cancer. Methods A total of 80 colorectal cancer patients treated at our hospital were selected as research subjects. According to the random number table method, patients were divided into a control group (mFOLFOX6 plus bevacizumab) and a combination group (mFOLFOX6 plus bevacizumab after deep hyperthermia treatment), with 40 patients in each group. After six cycles of treatment, the objective response rate (ORR), disease control rate (DCR), levels of serum tumor markers carcinoembryonic antigen (CEA), vascular epidermal growth factor (VEGF), Karnofsky performance status (KPS) scores, and the occurrence of adverse events were compared between the two groups. Results After six cycles of treatment, the ORR in the combination group was higher than that in the control group, but the difference was not statistically significant (P>0.05). The DCR in the combination group was significantly higher than that in the control group (P<0.05). The serum CEA levels in the control and combination groups after treatment were significantly lower than those before treatment, and the serum CEA and VEGF levels in the combination group were significantly lower than those in the control group (all P<0.001). The KPS scores in both groups after treatment were higher than those before treatment, and the KPS scores in the combination group after treatment were significantly higher than those in the control group (all P<0.001). The incidence of fatigue and pain in the combination group was significantly lower than that in the control group (P<0.05). Conclusion mFOLFOX6 plus bevacizumab after deep hyperthermia is effective in advanced colorectal cancer patients, which can effectively improve their quality of life, and the adverse events are controllable and tolerable. A randomized or prospective trial will be required to further prove these data and explore its potentiality, especially if compared to conventional treatment.
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Affiliation(s)
| | | | | | | | - Shenzha Liu
- Department of Oncology, Jingjiang People’s Hospital Affiliated with Yangzhou University, Jingjiang, China
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14
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Chitkara A, Kaur N, Desai A, Mehta D, Anamika F, Sarkar S, Gowda N, Sethi P, Thawani R, Chen EY. Risks of hypertension and thromboembolism in patients receiving bevacizumab with chemotherapy for colorectal cancer: A systematic review and meta-analysis. Cancer Med 2023; 12:21579-21591. [PMID: 38069531 PMCID: PMC10757147 DOI: 10.1002/cam4.6662] [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: 05/22/2023] [Revised: 09/12/2023] [Accepted: 10/03/2023] [Indexed: 12/31/2023] Open
Abstract
BACKGROUND Guidelines show that for metastatic colorectal cancer (mCRC), a combination of three-drug regimens, fluorouracil, leucovorin, and oxaliplatin and bevacizumab (BVZ), is one of the first-line standard therapies. BVZ is generally well tolerated; however, it is associated with infrequent, life-threatening side effects such as severe hypertension (HTN) (5%-18%), Grade ≥3 arterial thromboembolism (ATE) (2.6%), Grade ≥3 hemorrhagic events (1.2%-4.6%), and gastrointestinal perforation (0.3%-2.4%). This meta-analysis aims to evaluate the additive risk of BVZ-induced severe HTN and thromboembolism when BVZ is combined with a standard chemotherapy regime in patients with mCRC. METHODS Our search was conducted from January 29, 2022, to February 22, 2022, through databases of PubMed, clinicaltrial.gov, EMBASE, Web of Science, and Cochrane Library. Data analysis from randomized controlled trials (RCTs) and clinical trials was conducted using Review Manager V.5.4, comparing BVZ-chemotherapy to chemotherapy only, focusing on cardiovascular AE such as HTN and arterial and venous thromboembolism. RESULTS The analysis from 26 clinical trials and RCTs showed that the odds of HTN were about four times higher, and ATE subgroup analysis of 11 studies showed over two times higher odds of ATE in patients being treated with BVZ compared to the chemotherapy-only group. CONCLUSION BVZ, when added to the standard chemotherapy regimen for mCRC, was associated with higher odds of developing HTN and thromboembolism, specifically ATE, than the chemotherapy-only group. Our findings are significant as they provide vital information in analyzing the risk-benefit ratio of adding BVZ to the standard chemotherapy regime in patients with mCRC, especially in patients with vascular comorbidities.
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Affiliation(s)
- Akshit Chitkara
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Nirmaljot Kaur
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Aditya Desai
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Devanshi Mehta
- Loma Linda UniversityCalifornia in Internal MedicineCaliforniaUSA
| | - Fnu Anamika
- Internal MedicineHackensack Meridian Ocean UniversityBrickNew JerseyUSA
| | - Srawani Sarkar
- Research LabAlbert Einstein College of MedicineNew YorkNew YorkUSA
| | - Nandini Gowda
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Prabhdeep Sethi
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Rajat Thawani
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
| | - Emerson Y. Chen
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
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15
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Conway JW, Braden J, Lo SN, Scolyer RA, Carlino MS, Menzies AM, Long GV, da Silva IP. VEGF Inhibitors Improve Survival Outcomes in Patients with Liver Metastases across Cancer Types-A Meta-Analysis. Cancers (Basel) 2023; 15:5012. [PMID: 37894379 PMCID: PMC10605052 DOI: 10.3390/cancers15205012] [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: 09/01/2023] [Revised: 09/26/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Liver metastases are associated with poor prognosis across cancers. Novel treatment strategies to treat patients with liver metastases are needed. This meta-analysis aimed to assess the efficacy of vascular endothelial growth factor inhibitors in patients with liver metastases across cancers. METHODS A systematic search of PubMed, Cochrane CENTRAL, and Embase was performed between January 2000 and April 2023. Randomized controlled trials of patients with liver metastases comparing standard of care (systemic therapy or best supportive care) with or without vascular endothelial growth factor inhibitors were included in the study. Outcomes reported included progression-free survival and overall survival. RESULTS A total of 4445 patients with liver metastases from 25 randomized controlled trials were included in this analysis. The addition of vascular endothelial growth factor inhibitors to standard systemic therapy or best supportive care was associated with superior progression-free survival (HR = 0.49; 95% CI, 0.40-0.61) and overall survival (HR = 0.83; 95% CI, 0.74-0.93) in patients with liver metastases. In a subgroup analysis of patients with versus patients without liver metastases, the benefit with vascular endothelial growth factor inhibitors was more pronounced in the group with liver metastases (HR = 0.44) versus without (HR = 0.57) for progression-free survival, but not for overall survival. CONCLUSION The addition of vascular endothelial growth factor inhibitors to standard management improved survival outcomes in patients with liver metastasis across cancers.
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Affiliation(s)
- Jordan W. Conway
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
| | - Jorja Braden
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
| | - Serigne N. Lo
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Richard A. Scolyer
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
- Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
- NSW Health Pathology, Sydney, NSW 2099, Australia
| | - Matteo S. Carlino
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW 2148, Australia
| | - Alexander M. Menzies
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Royal North Shore Hospital, Sydney, NSW 2065, Australia
- Mater Hospital, Sydney, NSW 2060, Australia
| | - Georgina V. Long
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
- Royal North Shore Hospital, Sydney, NSW 2065, Australia
- Mater Hospital, Sydney, NSW 2060, Australia
| | - Ines Pires da Silva
- Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, North Sydney, NSW 2065, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW 2050, Australia
- Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, NSW 2148, Australia
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16
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Otsu S, Hironaka S. Current Status of Angiogenesis Inhibitors as Second-Line Treatment for Unresectable Colorectal Cancer. Cancers (Basel) 2023; 15:4564. [PMID: 37760533 PMCID: PMC10526327 DOI: 10.3390/cancers15184564] [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: 08/11/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer is the third most common disease and the second most common cause of death around the world. The drug for second-line treatment depends on the drugs used in first-line treatment and the biomarker status. As biomarkers, the RAS gene, BRAF gene, and dMMR/MSI-H, TMB-H, and HER2 statuses have been established in clinical practice, and the corresponding molecularly targeted therapeutic agents are selected based on the biomarker status. Given the frequency of biomarkers, it is assumed that when patients move on to second-line treatment, an angiogenesis inhibitor is selected in many cases. For second-line treatment, three angiogenesis inhibitors, bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are available, and one of them is combined with cytotoxic agents. These three angiogenesis inhibitors are known to inhibit angiogenesis through different mechanisms of action. Although no useful biomarkers have been established for the selection of angiogenesis inhibitors, previous biomarker studies have suggested that angiogenesis-related factors such as VEGF-A and VEGF-D might be predictors of the therapeutic efficacy of angiogenesis inhibitors. These biomarkers are measured as protein levels in plasma and are considered to be promising biomarkers. We consider that the rationale for selecting among these three angiogenesis inhibitors should be clarified to benefit patients.
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Affiliation(s)
- Satoshi Otsu
- Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu City 879-5593, Oita, Japan
| | - Shuichi Hironaka
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka-shi 181-8611, Tokyo, Japan
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17
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Deng J, Zeng X, Hu W, Yue T, Luo Z, Zeng L, Li P, Chen J. Different doses of bevacizumab in combination with chemotherapy for advanced colorectal cancer: a meta-analysis and Bayesian analysis. Int J Colorectal Dis 2023; 38:164. [PMID: 37289304 DOI: 10.1007/s00384-023-04442-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/21/2023] [Indexed: 06/09/2023]
Abstract
OBJECTIVE The aim of the present study was to explore the incremental benefit of bevacizumab (Bev) in the treatment of advanced colorectal cancer (CRC) with different doses. METHODS A literature search of eight electronic databases (China National Knowledge Infrastructure, Wanfang databases, Chinese Biomedical Database, VIP medicine information, Cochrane Library, MEDLINE, PubMed, and EMBASE) was conducted from database creation to December 2022. Randomized controlled trials (RCTs) that compared Bev at various dosages + chemotherapy (CT) versus placebo (or blank control) + CT were selected. The overall survival (OS), progression-free survival (PFS), overall response rate (ORR; complete response [CR] + partial response [PR]), and grade ≥ 3 adverse events (AEs) were integrated first by pooled analysis. The likelihood of ideal dosage of Bev was then ranked using random effects within Bayesian analysis. RESULTS Twenty-six RCTs involving 18,261 patients met the inclusion criteria. OS increased significantly after using 5 mg (HR: 0.87, 95% CI 0.75 to 1.00) and 10 mg dosages of Bev (HR: 0.75, 95% CI 0.66 to 0.85) with CT, but statistical significance was not attained for the 7.5 mg dose (HR: 0.95, 95% CI 0.83 to 1.08). A significantly increased in PFS with doses of 5 mg (HR: 0.69, 95% CI 0.58 to 0.83), 7.5 mg (HR: 0.81, 95% CI 0.66 to 1.00), and 10 mg (HR: 0.60, 95% CI 0.53 to 0.68). ORR distinctly increased after 5 mg (RR: 1.34, 95% CI 1.15 to 1.55), 7.5 mg (RR: 1.25, 95% CI 1.05 to 1.50), and10 mg (RR: 2.27, 95% CI 1.82 to 2.84) doses were administered. Grade ≥ 3 AEs increased clearly in 5 mg (RR: 1.11, 95% CI 1.04 to 1.20) compared to 7.5 mg (RR: 1.05, 95% CI 0.82 to 1.35) and 10 mg (RR: 1.15, 95% CI 0.98 to 1.36). Bayesian analysis demonstrated that 10 mg Bev obtained the maximum time of OS (HR: 0.75, 95% CrI 0.58 to 0.97; probability rank = 0.05) indirectly compared to 5 mg and 7.5 mg Bev. Compared with 5 mg and 7.5 mg Bev, 10 mg Bev also holds the longest duration for PFS (HR: 0.59, 95% CrI 0.43 to 0.82; probability rank = 0.00). In terms of ORR, 10 mg Bev holds the maximum frequency (RR: 2.02, 95% CrI 1.52 to 2.66; probability rank = 0.98) in comparison to 5 mg and 7.5 mg Bev clearly. For grade ≥ 3 AEs, 10 mg Bev has the maximum incidence (RR: 1.15, 95% CrI 0.95 to 1.40, probability rank = 0.67) in comparison to other doses of Bev. CONCLUSION The study suggests that 10 mg dose Bev could be more effective in treating advanced CRC in efficacy, but 5 mg Bev could be more safer in terms of safety.
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Affiliation(s)
- Jia Deng
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Xinglin Zeng
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenting Hu
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Tinghui Yue
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Zicheng Luo
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Lian Zeng
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Ping Li
- Colorectal and Anal Surgery, the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No 71 Baoshan North Road, Guiyang, 550001, China.
| | - Jiang Chen
- Colorectal and Anal Surgery, the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No 71 Baoshan North Road, Guiyang, 550001, China.
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Abudureheiyimu N, Wu Y, Li Q, Zhang P, Ma F, Yuan P, Luo Y, Fan Y, Chen S, Cai R, Li Q, Han Y, Xu H, Wang Y, Wang J, Xu B. Docetaxel plus S-1 versus docetaxel plus capecitabine as first-line treatment for advanced breast cancer patients: a prospective randomized phase II study. JOURNAL OF THE NATIONAL CANCER CENTER 2023; 3:115-120. [PMID: 39035725 PMCID: PMC11256714 DOI: 10.1016/j.jncc.2023.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 04/24/2023] [Accepted: 05/17/2023] [Indexed: 07/23/2024] Open
Abstract
Background This study was conducted to evaluate the efficacy and safety of docetaxel/S-1 (TS) compared with docetaxel/capecitabine (TX) as a first-line treatment for advanced breast cancer. Methods Patients with advanced metastatic breast cancer were randomly divided into the TS group (n = 54) and the TX group (n = 57) for first-line chemotherapy from August 2015 to April 2019 (ClinicalTrials.org registration no. NCT02947061). Following the completion of combination therapy, patients without progression received S-1 or capecitabine maintenance treatment. The primary end point was progression-free survival (PFS). Results Among 111 enrolled patients, the median PFS did not differ significantly between the TS group and the TX group (TS vs. TX, 9.0 vs. 7.4 months, P = 0.365, 95% confidence interval [CI]: 0.50-1.11, hazard ratio [HR]: 0.75). There was also no statistically significant difference in median overall survival (OS) between the two groups (TS vs. TX, 40.2 vs. 41.3 months, P = 0.976). In addition, visceral metastasis and metastasis sites, such as the liver or lung, did not lead to a significant effect on PFS and OS. The two regimens showed no significant difference in adverse events, except hand-foot syndrome, which predominated in the TX group (38.6% vs. 7.4%, P = 0.001), and diarrhea (24.1% vs. 3.6%, P = 0.003) and elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels (14.8% vs. 3.5%, P = 0.049), which were more frequent in the TS group. Conclusions The TS and TX regimens demonstrated similar efficacy and safety for the first-line treatment of advanced breast cancer. The TS regimen had fewer cases of severe hand-foot syndrome than the TX regimen, representing an effective alternative option to the TX regimen. Further studies are warranted to define the efficacy and safety of this strategy in real-world settings.
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Affiliation(s)
- Nilupai Abudureheiyimu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yun Wu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qing Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pin Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fei Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Peng Yuan
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Luo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Fan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shanshan Chen
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruigang Cai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiao Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiqun Han
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hangcheng Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiayu Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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19
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Rejali L, Seifollahi Asl R, Sanjabi F, Fatemi N, Asadzadeh Aghdaei H, Saeedi Niasar M, Ketabi Moghadam P, Nazemalhosseini Mojarad E, Mini E, Nobili S. Principles of Molecular Utility for CMS Classification in Colorectal Cancer Management. Cancers (Basel) 2023; 15:2746. [PMID: 37345083 PMCID: PMC10216373 DOI: 10.3390/cancers15102746] [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: 03/21/2023] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 06/23/2023] Open
Abstract
Colorectal cancer (CRC) is the second cause of cancer-related deaths in both sexes globally and presents different clinical outcomes that are described by a range of genomic and epigenomic alterations. Despite the advancements in CRC screening plans and treatment strategies, the prognosis of CRC is dismal. In the last two decades, molecular biomarkers predictive of prognosis have been identified in CRC, although biomarkers predictive of treatment response are only available for specific biological drugs used in stage IV CRC. Translational clinical trials mainly based on "omic" strategies allowed a better understanding of the biological heterogeneity of CRCs. These studies were able to classify CRCs into subtypes mainly related to prognosis, recurrence risk, and, to some extent, also to treatment response. Accordingly, the comprehensive molecular characterizations of CRCs, including The Cancer Genome Atlas (TCGA) and consensus molecular subtype (CMS) classifications, were presented to improve the comprehension of the genomic and epigenomic landscapes of CRCs for a better patient management. The CMS classification obtained by the CRC subtyping consortium categorizes CRC into four consensus molecular subtypes (CMS1-4) characterized by different prognoses. In this review, we discussed the CMS classification in different settings with a focus on its relationships with precursor lesions, tumor immunophenotype, and gut microbiota, as well as on its role in predicting prognosis and/or response to pharmacological treatments, as a crucial step towards precision medicine.
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Affiliation(s)
- Leili Rejali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 19875-17411, Iran; (L.R.); (R.S.A.); (N.F.); (H.A.A.); (M.S.N.); (P.K.M.)
| | - Romina Seifollahi Asl
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 19875-17411, Iran; (L.R.); (R.S.A.); (N.F.); (H.A.A.); (M.S.N.); (P.K.M.)
| | - Fatemeh Sanjabi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran P.O. Box 14496-14535, Iran;
| | - Nayeralsadat Fatemi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 19875-17411, Iran; (L.R.); (R.S.A.); (N.F.); (H.A.A.); (M.S.N.); (P.K.M.)
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 19875-17411, Iran; (L.R.); (R.S.A.); (N.F.); (H.A.A.); (M.S.N.); (P.K.M.)
| | - Mahsa Saeedi Niasar
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 19875-17411, Iran; (L.R.); (R.S.A.); (N.F.); (H.A.A.); (M.S.N.); (P.K.M.)
| | - Pardis Ketabi Moghadam
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran P.O. Box 19875-17411, Iran; (L.R.); (R.S.A.); (N.F.); (H.A.A.); (M.S.N.); (P.K.M.)
| | - Ehsan Nazemalhosseini Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Yaman Street, Chamran Expressway, Tehran P.O. Box 19857-17411, Iran;
| | - Enrico Mini
- Department of Health Sciences, University of Florence, Viale Pieraccini, 6, 50139 Firenze, Italy;
| | - Stefania Nobili
- Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini, 6, 50139 Firenze, Italy
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20
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Lau DK, Fong C, Arouri F, Cortez L, Katifi H, Gonzalez-Exposito R, Razzaq MB, Li S, Macklin-Doherty A, Hernandez MA, Hubank M, Fribbens C, Watkins D, Rao S, Chau I, Cunningham D, Starling N. Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre. BMC Cancer 2023; 23:380. [PMID: 37101114 PMCID: PMC10131438 DOI: 10.1186/s12885-023-10857-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 04/17/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. METHODS Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25-50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. RESULTS Between 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5-75%) for DPYD heterozygous carriers and 93.2% (42.9-100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924). CONCLUSIONS Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.
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Affiliation(s)
- David K Lau
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Caroline Fong
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Faten Arouri
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Lillian Cortez
- Department of Pharmacy, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Hannah Katifi
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Reyes Gonzalez-Exposito
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Muhammad Bilal Razzaq
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Su Li
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Aislinn Macklin-Doherty
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | | | - Michael Hubank
- Centre for Molecular Pathology, Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK
| | - Charlotte Fribbens
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - David Watkins
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Sheela Rao
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Ian Chau
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - David Cunningham
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK
| | - Naureen Starling
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London and Sutton, UK.
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21
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Esmaeilniakooshkghazi A, Pham E, George SP, Ahrorov A, Villagomez FR, Byington M, Mukhopadhyay S, Patnaik S, Conrad JC, Naik M, Ravi S, Tebbutt N, Mooi J, Reehorst CM, Mariadason JM, Khurana S. In colon cancer cells fascin1 regulates adherens junction remodeling. FASEB J 2023; 37:e22786. [PMID: 36786724 DOI: 10.1096/fj.202201454r] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/21/2022] [Accepted: 01/10/2023] [Indexed: 02/15/2023]
Abstract
Adherens junctions (AJs) are a defining feature of all epithelial cells. They regulate epithelial tissue architecture and integrity, and their dysregulation is a key step in tumor metastasis. AJ remodeling is crucial for cancer progression, and it plays a key role in tumor cell survival, growth, and dissemination. Few studies have examined AJ remodeling in cancer cells consequently, it remains poorly understood and unleveraged in the treatment of metastatic carcinomas. Fascin1 is an actin-bundling protein that is absent from the normal epithelium but its expression in colon cancer is linked to metastasis and increased mortality. Here, we provide the molecular mechanism of AJ remodeling in colon cancer cells and identify for the first time, fascin1's function in AJ remodeling. We show that in colon cancer cells fascin1 remodels junctional actin and actomyosin contractility which makes AJs less stable but more dynamic. By remodeling AJs fascin1 drives mechanoactivation of WNT/β-catenin signaling and generates "collective plasticity" which influences the behavior of cells during cell migration. The impact of mechanical inputs on WNT/β-catenin activation in cancer cells remains poorly understood. Our findings highlight the role of AJ remodeling and mechanosensitive WNT/β-catenin signaling in the growth and dissemination of colorectal carcinomas.
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Affiliation(s)
| | - Eric Pham
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Sudeep P George
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Afzal Ahrorov
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Fabian R Villagomez
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Michael Byington
- Department of Chemical and Bimolecular Engineering, University of Houston, Houston, Texas, USA
| | - Srijita Mukhopadhyay
- Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA
| | - Srinivas Patnaik
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Jacinta C Conrad
- Department of Chemical and Bimolecular Engineering, University of Houston, Houston, Texas, USA
| | - Monali Naik
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Saathvika Ravi
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA
| | - Niall Tebbutt
- Gastrointestinal Cancers Programs, Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia
| | - Jennifer Mooi
- Gastrointestinal Cancers Programs, Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia
| | - Camilla M Reehorst
- Gastrointestinal Cancers Programs, Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia
| | - John M Mariadason
- Gastrointestinal Cancers Programs, Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia
| | - Seema Khurana
- Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA.,School of Health Professions, Baylor College of Medicine, Houston, Texas, USA
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22
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de With M, van Doorn L, Maasland DC, Mulder TAM, Oomen-de Hoop E, Mostert B, Homs MYV, El Bouazzaoui S, Mathijssen RHJ, van Schaik RHN, Bins S. Capecitabine-induced hand-foot syndrome: A pharmacogenetic study beyond DPYD. Biomed Pharmacother 2023; 159:114232. [PMID: 36630849 DOI: 10.1016/j.biopha.2023.114232] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/05/2023] [Accepted: 01/08/2023] [Indexed: 01/11/2023] Open
Abstract
AIM OF THE STUDY Occurrence of hand-foot syndrome (HFS) during capecitabine treatment often results in treatment interruptions (26 %) or treatment discontinuation (17 %), and can severely decrease quality of life. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism - other than DPYD - are associated with an increased risk for capecitabine-induced HFS. METHODS Patients treated with capecitabine according to standard of care were enrolled after providing written informed consent for genotyping purposes. Prospectively collected blood samples were used to extract genomic DNA, which was subsequently genotyped for SNPs in CES1, CES2 and CDA. SNPs and clinical baseline factors that were univariably associated with HFS with P ≤ 0.10, were tested in a multivariable model using logistic regression. RESULTS Of the 446 patients eligible for analysis, 146 (32.7 %) developed HFS, of whom 77 patients (17.3 %) experienced HFS ≥ grade 2. In the multivariable model, CES1 1165-33 C>A (rs2244613, minor allele frequency 19 %) and CDA 266 + 242 A>G (rs10916825, minor allele frequency 35 %) variant allele carriers were at higher risk of HFS ≥ grade 2 (OR 1.888; 95 %CI 1.075-3.315; P = 0.027 and OR 1.865; 95 %CI 1.087-3.200; P = 0.024, respectively). CONCLUSIONS We showed that CES1 1165-33 C>A and CDA 266 + 242 A>G are significantly associated with HFS grade 2 and grade 3 in patients treated with capecitabine. Prospective studies should assess whether this increased risk can be mitigated in carriers of these SNPs, when pre-emptive genotyping is being followed by dose adjustment or by alternative treatment by a fluoropyrimidine that is not substrate to CES1, such as S1.
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Affiliation(s)
- Mirjam de With
- Dep. of Medical Oncology, Erasmus MC Cancer Institute, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands; Dep. of Clinical Chemistry, Erasmus University Medical Center, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Leni van Doorn
- Dep. of Medical Oncology, Erasmus MC Cancer Institute, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Demi C Maasland
- Dep. of Medical Oncology, Erasmus MC Cancer Institute, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Tessa A M Mulder
- Dep. of Clinical Chemistry, Erasmus University Medical Center, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Esther Oomen-de Hoop
- Dep. of Medical Oncology, Erasmus MC Cancer Institute, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Bianca Mostert
- Dep. of Medical Oncology, Erasmus MC Cancer Institute, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Marjolein Y V Homs
- Dep. of Medical Oncology, Erasmus MC Cancer Institute, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Samira El Bouazzaoui
- Dep. of Clinical Chemistry, Erasmus University Medical Center, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Ron H J Mathijssen
- Dep. of Medical Oncology, Erasmus MC Cancer Institute, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Ron H N van Schaik
- Dep. of Clinical Chemistry, Erasmus University Medical Center, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Sander Bins
- Dep. of Medical Oncology, Erasmus MC Cancer Institute, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
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23
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André T, Falcone A, Shparyk Y, Moiseenko F, Polo-Marques E, Csöszi T, Campos-Bragagnoli A, Liposits G, Chmielowska E, Aubel P, Martín L, Fougeray R, Amellal N, Saunders MP. Trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer ineligible for intensive therapy (SOLSTICE): a randomised, open-label phase 3 study. Lancet Gastroenterol Hepatol 2023; 8:133-144. [PMID: 36470291 DOI: 10.1016/s2468-1253(22)00334-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 12/05/2022]
Abstract
BACKGROUND Trifluridine-tipiracil plus bevacizumab has shown efficacy in previous phase 2 studies including patients with unresectable metastatic colorectal cancer. We aimed to investigate first-line trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab in patients with unresectable metastatic colorectal cancer ineligible for intensive treatment. METHODS In this open-label, randomised, phase 3 study, we enrolled patients aged 18 years and older with histologically confirmed metastatic colorectal cancer, ineligible for full-dose doublet or triplet chemotherapy and curative resection across 25 countries and regions. Participants were randomly allocated (1:1) to trifluridine-tipiracil plus bevacizumab or capecitabine plus bevacizumab until disease progression or unacceptable toxicity using an interactive web response system, stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), primary tumour location (right vs left colon), and the main reason for not being a candidate for intensive therapy (clinical condition vs non-clinical condition). The primary endpoint was investigator-assessed progression-free survival, defined as the time from randomisation to radiological progression or death from any cause, in the intention-to-treat population. Safety was assessed in all patients having taken at least one dose of the study drug. The trial is ongoing, findings presented here are those of the primary analysis of progression-free survival, conducted after 629 events had occurred. This study is registered with ClinicalTrials.gov, NCT03869892. FINDINGS Between March 21, 2019, and Sept 14, 2020, 856 patients (54% male, 46% female) were randomly assigned to trifluridine-tipiracil plus bevacizumab (n=426) or capecitabine plus bevacizumab (n=430). After a median follow-up of 16·6 months (95% CI 16·5-17·1), the hazard ratio for progression-free survival for trifluridine-tipiracil plus bevacizumab versus capecitabine plus bevacizumab was 0·87 (0·75-1·02; p=0·0464; protocol-defined significance level of p=0·021 not met). Investigator-assessed median progression-free survival was 9·4 months (95% CI 9·1-10·9) with trifluridine-tipiracil plus bevacizumab versus 9·3 months (8·9-9·8) with capecitabine plus bevacizumab. The most common grade 3 and higher treatment-emergent adverse events were neutropenia (220 [52%] of 423 patients in the trifluridine-tipiracil plus bevacizumab group vs six [1%] of 427 in the capecitabine plus bevacizumab group), decreased neutrophil count (78 [18%] vs four [<1%]), anaemia (60 [14%] vs 16 [4%]), and hand-foot syndrome (none vs 61 [15%]). Nine deaths (five in the trifluridine-tipiracil plus bevacizumab group and four in the capecitabine plus bevacizumab group) were treatment related. INTERPRETATION First-line trifluridine-tipiracil plus bevacizumab was not superior to capecitabine plus bevacizumab in this population. As expected, the safety profile differed between the two treatments, but there were no new safety concerns. Trifluridine-tipiracil plus bevacizumab represents a feasible alternative to capecitabine plus bevacizumab in this population. FUNDING Servier International Research Institute, Suresnes, France.
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Affiliation(s)
- Thierry André
- Sorbonne University and Saint-Antoine Hospital, Department of Medical Oncology, Paris, France.
| | | | | | - Fedor Moiseenko
- Saint Petersburg Clinical Research and Practical Centre for Specialized Types of Medical Care (Oncological), St Petersburg, Russia
| | | | - Tibor Csöszi
- Géza Hetényi Hospital-Jász-Nagykun-Szolnok County Hospital Oncology Centre, Szolnok, Hungary
| | | | | | - Ewa Chmielowska
- Specialistic Oncologic Hospital Nu-Med, Tomaszów Mazowiecki, Poland
| | - Paul Aubel
- Servier International Research Institute, Suresnes, France
| | - Lourdes Martín
- Servier International Research Institute, Suresnes, France
| | - Ronan Fougeray
- Servier International Research Institute, Suresnes, France
| | - Nadia Amellal
- Servier International Research Institute, Suresnes, France
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24
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Zhuang Y, Liu K, He Q, Gu X, Jiang C, Wu J. Hypoxia signaling in cancer: Implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e203. [PMID: 36703877 PMCID: PMC9870816 DOI: 10.1002/mco2.203] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/14/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023] Open
Abstract
Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia-targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.
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Affiliation(s)
- Yan Zhuang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Kua Liu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Qinyu He
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
| | - Xiaosong Gu
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
| | - Chunping Jiang
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
| | - Junhua Wu
- State Key Laboratory of Pharmaceutical BiotechnologyNational Institute of Healthcare Data Science at Nanjing UniversityJiangsu Key Laboratory of Molecular MedicineMedicineMedical School of Nanjing UniversityNanjing UniversityNanjingChina
- Microecological, Regenerative and Microfabrication Technical Platform for Biomedicine and Tissue EngineeringJinan Microecological Biomedicine Shandong LaboratoryJinan CityChina
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Julka PK, Arya D, Gupta K. Long-Term 5-Year Response to Pembrolizumab, Bevacizumab, and Capecitabine Regimen in a Metastatic Colon Cancer Patient with MSI-High and KRAS Mutation: Case Report. Case Rep Oncol 2023; 16:1020-1027. [PMID: 37900837 PMCID: PMC10601776 DOI: 10.1159/000533760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 08/22/2023] [Indexed: 10/31/2023] Open
Abstract
With an estimated 1.88 million new cases and 0.92 million deaths in 2020, colorectal cancer accounts for nearly one-tenth of all new cancer and cancer-related deaths worldwide. Nearly half of the patients of colorectal cancer are diagnosed with metastatic or inoperable disease with a very dismal 5-year survival rate. Chemotherapy, targeted therapy, and immunotherapy have been used to treat metastatic disease, either alone or in combination. We present a case of recurrent metastatic colon carcinoma with KRAS exon 2 mutation and high microsatellite instability that was treated with a combination regimen of bevacizumab, capecitabine oral chemotherapy, and pembrolizumab immunotherapy. At nearly 5 years of treatment, the patient is alive with good performance status and improved quality of life owing to a favorable response to the molecular profiling-based treatment approach.
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Affiliation(s)
- Pramod Kumar Julka
- Department of Medical Oncology, Max Institute of Cancer Care, Delhi, India
| | - Deepika Arya
- Department of Medical Oncology, Max Institute of Cancer Care, Delhi, India
| | - Kush Gupta
- Department of Clinical Operations, Catalyst Clinical Services Pvt. Ltd., Delhi, India
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Cervantes A, Adam R, Roselló S, Arnold D, Normanno N, Taïeb J, Seligmann J, De Baere T, Osterlund P, Yoshino T, Martinelli E. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023; 34:10-32. [PMID: 36307056 DOI: 10.1016/j.annonc.2022.10.003] [Citation(s) in RCA: 660] [Impact Index Per Article: 330.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/06/2022] [Accepted: 10/06/2022] [Indexed: 02/08/2023] Open
Affiliation(s)
- A Cervantes
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - R Adam
- AP-HP Hôpital Paul Brousse, Université Paris-Saclay, ER "Chronothérapie, Cancers, Transplantation", Villejuif, France
| | - S Roselló
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - D Arnold
- Department of Oncology and Hematology, Asklepios Tumourzentrum Hamburg, AK Altona, Hamburg, Germany
| | - N Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumouri, 'Fondazione G. Pascale'-IRCCS, Naples, Italy
| | - J Taïeb
- Department of Gastroenterology and GI Oncology, Georges Pompidou European Hospital, Assitance Publique-Hôpitaux de Paris AP-HP Paris Centre, Paris, France; Paris Cancer Institute SIRIC CARPEM, Centre de Recherche des Cordeliers, Université Paris-Cité, Paris, France
| | - J Seligmann
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - T De Baere
- Department of Interventional Radiology, Gustave Roussy, Villejuif, France; University of Paris-Saclay, UFR Médecine Le Kremlin-Bicêtre, Le Kremlin-Bicêtre, France; Centre d'Investigation Clinique BIOTHERIS, INSERM CIC1428, Villejuif, France
| | - P Osterlund
- Tampere University Hospitals and University, Tampere, Finland; Tema Cancer/GI-oncology, Karolinska Comprehensive Cancer Centre, Karolinska Institute, Solna, Sweden
| | - T Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - E Martinelli
- Department of Precision Medicine, Oncology Unit, Università della Campania "L. Vanvitelli", Naples, Italy
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Ferreira CS, Babitzki G, Klaman I, Krieter O, Lechner K, Bendell J, Vega Harring S, Heil F. Predictive potential of angiopoietin-2 in a mCRC subpopulation treated with vanucizumab in the McCAVE trial. Front Oncol 2023; 13:1157596. [PMID: 37207143 PMCID: PMC10190963 DOI: 10.3389/fonc.2023.1157596] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/31/2023] [Indexed: 05/21/2023] Open
Abstract
Introduction Angiopoetin-2 (Ang-2) is a key mediator of tumour angiogenesis. When upregulated it is associated with tumour progression and poor prognosis. Anti-vascular endothelial growth factor (VEGF) therapy has been widely used in the treatment of metastatic colorectal cancer (mCRC). The potential benefit of combined inhibition of Ang-2 and VEGF-A in previously untreated patients with mCRC was evaluated in the phase II McCAVE study (NCT02141295), assessing vanucizumab versus bevacizumab (VEGF-A inhibitor), both in combination with mFOLFOX-6 (modified folinic acid [leucovorin], fluorouracil and oxaliplatin) chemotherapy. To date, there are no known predictors of outcome of anti-angiogenic treatment in patients with mCRC. In this exploratory analysis, we investigate potential predictive biomarkers in baseline samples from McCAVE participants. Methods Tumour tissue samples underwent immunohistochemistry staining for different biomarkers, including Ang-2. Biomarker densities were scored on the tissue images using dedicated machine learning algorithms. Ang-2 levels were additionally assessed in plasma. Patients were stratified by KRAS mutation status determined using next generation sequencing. Median progression-free survival (PFS) for each treatment group by biomarker and KRAS mutation was estimated using Kaplan-Meier plots. PFS hazard ratios (and 95% confidence intervals) were compared using Cox regression. Results Overall low tissue baseline levels of Ang-2 were associated with longer PFS, especially in patients with wild-type KRAS status. In addition, our analysis identified a new subgroup of patients with KRAS wild-type mCRC and high levels of Ang-2 in whom vanucizumab/mFOLFOX-6 prolonged PFS significantly (log-rank p=0.01) by ~5.5 months versus bevacizumab/mFOLFOX-6. Similar findings were seen in plasma samples. Discussion This analysis demonstrates that additional Ang-2 inhibition provided by vanucizumab shows a greater effect than single VEGF-A inhibition in this subpopulation. These data suggest that Ang-2 may be both a prognostic biomarker in mCRC and a predictive biomarker for vanucizumab in KRAS wild-type mCRC. Thus, this evidence can potentially support the establishment of more tailored treatment approaches for patients with mCRC.
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Affiliation(s)
- Cláudia S. Ferreira
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
- *Correspondence: Cláudia S. Ferreira, ; Galina Babitzki,
| | - Galina Babitzki
- PHCS Biostatistics & Data Management, Roche Innovation Center Munich, Penzberg, Germany
- *Correspondence: Cláudia S. Ferreira, ; Galina Babitzki,
| | - Irina Klaman
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Oliver Krieter
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Katharina Lechner
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Johanna Bendell
- Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, United States
| | - Suzana Vega Harring
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Florian Heil
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
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Margalit O, Harmsen WS, Shacham-Shmueli E, Voss MM, Boursi B, Wagner AD, Cohen R, Olswold CL, Saltz LB, Goldstein DA, Hurwitz H, Tebbutt NC, Kabbinavar FF, Adams RA, Chibaudel B, Grothey A, Yoshino T, Zalcberg J, de Gramont A, Shi Q, Lenz HJ. Evaluating sex as a predictive marker for response to bevacizumab in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database. Eur J Cancer 2023; 178:162-170. [PMID: 36446161 DOI: 10.1016/j.ejca.2022.10.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma (mCRC), showing a benefit in males, while the effect in females is less significant. METHODS Data from 3369 patients with mCRC enrolled on four first-line randomised trials testing chemotherapy with or without bevacizumab (2000-2007) were pooled. Association between sex and progression-free survival and overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut point of 60 years to evaluate the possible role of menopausal-related effects. RESULTS Bevacizumab was associated with an improved median OS in males and females, with a 2.3- and 0.6-months benefit, respectively. Stratified by age, bevacizumab resulted in improved OS in males at both age categories. In females at or above the age of 60 (n = 731), bevacizumab resulted in improved OS. However, in females below the age of 60 (n = 634), OS benefit did not reach statistical significance (adjusted hazard ratio = 0.94, 95% confidence interval 0.74-1.20). CONCLUSIONS Our results confirmed the OS benefit from the addition of bevacizumab to first-line chemotherapy in mCRC in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no survival benefit. These findings could be used to relieve financial toxicity or be redistributed within healthcare systems for other health-related purposes.
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Affiliation(s)
- Ofer Margalit
- Sheba Medical Center, Ramat-Gan, Israel; Tel-Aviv University, Tel-Aviv, Israel.
| | - William S Harmsen
- Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, USA
| | | | - Molly M Voss
- Department of Quantitative Science Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Ben Boursi
- Sheba Medical Center, Ramat-Gan, Israel; Tel-Aviv University, Tel-Aviv, Israel
| | - Anna D Wagner
- Department of Oncology, Division of Medical Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Romain Cohen
- Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, USA; Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, F-75012 Paris, France; Sorbonne University, INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012 Paris, France
| | - Curtis L Olswold
- Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, USA
| | | | | | | | - Niall C Tebbutt
- University of Melbourne, Australia; Austin Health, Heidelberg, Victoria, Australia
| | - Fairooz F Kabbinavar
- David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | | | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Japan
| | - John Zalcberg
- Department of Medical Oncology, Alfred Health and School of Public Health, Monash University, Melbourne, Australia
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Qian Shi
- Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, USA
| | - Heinz-Josef Lenz
- Department of Gastrointestinal Oncology, Keck School of Medicine at USC, Los Angeles, CA, USA
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Sommerhäuser G, Kurreck A, Stintzing S, Heinemann V, von Weikersthal LF, Dechow T, Kaiser F, Karthaus M, Schwaner I, Fuchs M, König A, Roderburg C, Hoyer I, Quante M, Kiani A, Fruehauf S, Müller L, Reinacher-Schick A, Ettrich TJ, Stahler A, Modest DP. Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer. BMC Cancer 2022; 22:820. [PMID: 35897060 PMCID: PMC9327141 DOI: 10.1186/s12885-022-09892-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 07/13/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. METHODS FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. DISCUSSION To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy. TRIAL REGISTRATION EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.
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Affiliation(s)
- G Sommerhäuser
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - A Kurreck
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - S Stintzing
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany
| | - V Heinemann
- German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany
- Department of Hematology/Oncology, LMU Klinikum, University of Munich, Comprehensive Cancer Center Munich, Munich, Germany
| | | | - T Dechow
- Oncological Practice, Ravensburg, Germany
| | - F Kaiser
- Oncological Practice, Landshut, Germany
| | - M Karthaus
- Department of Hematology and Oncology, Klinikum Neuperlach/ Klinikum Harlaching, Munich, Germany
| | - I Schwaner
- Oncological Practice Kurfuerstendamm, Berlin, Germany
| | - M Fuchs
- Department of Gastroenterology, Hepatology, and Gastrointestinal Oncology, München Klinik Bogenhausen, Munich, Germany
| | - A König
- Department of Gastroenterology and Gastrointestinal Oncology Goettingen, University Medical Center Goettingen, Goettingen, Germany
| | - C Roderburg
- Department of Gastroenterology, Hepatology, and Infectiology, University Medical Center Duesseldorf, Duesseldorf, Germany
| | - I Hoyer
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - M Quante
- Department of Gastroenterology, Hepatology, Endocrinology, and Infectiology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
| | - A Kiani
- Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | - S Fruehauf
- Department of Hematology, Oncology, and Palliative Care, Klinik Dr. Hancken GmbH, Stade, Germany
| | - L Müller
- Onkologie UnterEms, Leer, Germany
| | - A Reinacher-Schick
- Department of Hematology, Oncology and Palliative Care, Ruhr-University Bochum, Bochum, Germany
| | - T J Ettrich
- Department of Internal Medicine, University Hospital Ulm, Ulm, Germany
| | - A Stahler
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - D P Modest
- Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
- German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany.
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Inada R, Nagasaka T, Shimokawa M, Ojima H, Noura S, Tanioka H, Munemoto Y, Shimada Y, Ishibashi K, Shindo Y, Mishima H, Okajima M, Yamaguchi Y. Phase 3 trial of sequential versus combination treatment in colorectal cancer: The C-cubed study. Eur J Cancer 2022; 169:166-178. [DOI: 10.1016/j.ejca.2022.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/18/2022] [Accepted: 04/03/2022] [Indexed: 11/03/2022]
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Zhou YW, Long YX, Liu X, Liu JY, Qiu M. Tumor calcification is associated with better survival in metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy. Future Oncol 2022; 18:2453-2464. [PMID: 35712899 DOI: 10.2217/fon-2021-1422] [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: 02/08/2023] Open
Abstract
Aims: The purpose was to investigate the correlation between calcification and outcome in metastatic colorectal cancer (mCRC) patients who received bevacizumab plus chemotherapy as the first-line treatment. Methods: A single retrospective cohort study was conducted with all diagnosed mCRC cases who received bevacizumab and chemotherapy as the first-line therapy. Results: Among all enrolled patients (n = 159), 31 had tumor calcification. The median overall survival and progression-free survival were significantly better in patients with tumor calcification than in those without calcification. A higher objective overall response rate was also observed in the tumor calcification group. On multivariate analysis, tumor calcification was independently associated with overall survival and progression-free survival. Conclusions: Tumor calcification was independently associated with improved survival in mCRC patients treated with bevacizumab plus chemotherapy.
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Affiliation(s)
- Yu-Wen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yi-Xiu Long
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xia Liu
- Department of Colorectal Cancer Center, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Ji-Yan Liu
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Colorectal Cancer Center, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
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32
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Qi W, Zhang Q. Identification and Validation of Immune Molecular Subtypes and Immune Landscape Based on Colon Cancer Cohort. Front Med (Lausanne) 2022; 9:827695. [PMID: 35602471 PMCID: PMC9121983 DOI: 10.3389/fmed.2022.827695] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/11/2022] [Indexed: 12/15/2022] Open
Abstract
BackgroundThe incidence and mortality rates of colon adenocarcinoma (COAD), which is the fourth most diagnosed cancer worldwide, are high. A subset of patients with COAD has shown promising responses to immunotherapy. However, the percentage of patients with COAD benefiting from immunotherapy is unclear. Therefore, gaining a better understanding of the immune milieu of colon cancer could aid in the development of immunotherapy and suitable combination strategies.MethodsIn this study, gene expression profiles and clinical follow-up data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and molecular subtypes were identified using the ConsensusClusterPlus package in R. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic value of immune subtypes. The graph structure learning method was used to reduce the dimension to reveal the internal structure of the immune system. Weighted correlation network analysis (WGCNA) was performed to identify immune-related gene modules. Finally, western blotting was performed to verify the gene expression patterns in COAD samples.ResultsThe results showed that 424 COAD samples could be divided into three subtypes based on 1921 immune cell-related genes, with significant differences in prognosis between subtypes. Furthermore, immune-related genes could be divided into five functional modules, each with a different distribution pattern of immune subtypes. Immune subtypes and gene modules were highly reproducible across many data sets. There were significant differences in the distribution of immune checkpoints, molecular markers, and immune characteristics among immune subtypes. Four core genes, namely, CD2, FGL2, LAT2, and SLAMF1, with prognostic significance were identified by WGCNA and univariate Cox analysis.ConclusionOverall, this study provides a conceptual framework for understanding the tumor immune microenvironment of colon cancer.
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van Dijk E, van Werkhoven E, Asher R, Mooi JK, Espinoza D, van Essen HF, van Tinteren H, van Grieken NCT, Punt CJA, Tebbutt NC, Ylstra B. Predictive value of chromosome 18q11.2-q12.1 loss for benefit from bevacizumab in metastatic colorectal cancer; a post-hoc analysis of the randomized phase III-trial AGITG-MAX. Int J Cancer 2022; 151:1166-1174. [PMID: 35489024 PMCID: PMC9545440 DOI: 10.1002/ijc.34061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/07/2022] [Accepted: 04/12/2022] [Indexed: 11/24/2022]
Abstract
The VEGF‐A monoclonal antibody bevacizumab is currently recommended for first‐line treatment of all metastatic colorectal cancer (mCRC) patients. Cost‐benefit ratio and side‐effects however necessitate patient selection. A large retrospective yet nonrandomized study showed that patients with loss of chromosome 18q11.2‐q12.1 in the tumor and treated with bevacizumab have 3 months improved median progression‐free (PFS) and overall survival (OS) benefit compared to patients without this loss and/or treatment modality. Implementation for loss of chromosome 18q11.2‐q12.1 as a marker in clinical practice mandates evidence in a randomized controlled trial for bevacizumab. Of the trials with randomization of chemotherapy vs chemotherapy with bevacizumab, the AGITG‐MAX trial was the only one with tumor materials available. Chromosome 18q11.2‐q12.1 copy number status was measured for 256 AGITG‐MAX trial patients and correlated with PFS according to a predefined analysis plan with marker‐treatment interaction as the primary end‐point. Chromosome 18q11.2‐q12.1 losses were detected in 71% of patients (181/256) characteristic for mCRC. Consistent with the nonrandomized study, significant PFS benefit of bevacizumab was observed in patients with chromosome 18q11.2‐q12.1 loss (P = .009), and not in patients without 18q loss (P = .67). Although significance for marker‐treatment interaction was not reached (Pinteraction = .28), hazard ratio and 95% confidence interval of this randomized cohort (HRinteraction = 0.72; 95% CI = 0.39‐1.32) shows striking overlap with the nonrandomized study cohorts (HRinteraction = 0.41; 95% CI = 0.32‐0.8) supported by a nonsignificant Cochrane χ2 test (P = .11) for heterogeneity. We conclude that post hoc analysis of the AGITG‐MAX RCT provides supportive evidence for chromosome 18q11.2‐q12.1 as a predictive marker for bevacizumab in mCRC patients.
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Affiliation(s)
- Erik van Dijk
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
| | - Erik van Werkhoven
- Biometrics Department, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Rebecca Asher
- Department of Biostatistics, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia
| | - Jennifer K Mooi
- Olivia Newton-John Cancer Research Institute, Heidelberg; Department of Medicine, University of Melbourne, Melbourne, Australia.,Peter MacCallum Cancer Institute, Melbourne, Australia
| | - David Espinoza
- Department of Biostatistics, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia
| | - Hendrik F van Essen
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
| | - Harm van Tinteren
- Trial and Datacenter, Princess Máxima Center for pedeatric oncology, Utrecht, The Netherlands
| | - Nicole C T van Grieken
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
| | - Cornelis J A Punt
- Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Epidemiology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands
| | - Niall C Tebbutt
- Department of Medical Oncology, Austin Health, Heidelberg, Australia.,Department of Surgery, University of Melbourne
| | - Bauke Ylstra
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
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Rinaldi I, Winston K, Vincent LD, Wicaksono A, Wardoyo MP, Nurrobi YAS, Leoni J. Overall Survival and Progression-Free Survival Comparison of Bevacizumab Plus Chemotherapy Combination Regiment versus Chemotherapy Only Regiment in Previously Untreated Metastatic Colorectal Cancer: Systematic Review and Meta-Analysis. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.9375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Colorectal cancer is the third-most common cancer in the world, in which 15%–25% of patients already had metastatic colorectal cancer (mCRC) at the time of diagnosis. The overall survival (OS) of mCRC is poor with the use of chemotherapy.
AIM: This systematic review and meta-analysis aim to examine the outcomes of OS and progression-free survival (PFS) of adding bevacizumab to different chemotherapy regiments compared to chemotherapy regiments only in the treatment of untreated mCRC.
METHODS: Literature searching was done in databases such as PubMed, EBSCO, SCOPUS, and ScienceDirect. The primary outcome measured in this systematic review and meta-analysis was OS, while the secondary outcome was PFS. Hazard ratio (HR) was used as the main summary measure with 95% confidence interval (CI). Publication bias was measured using a funnel plot.
RESULTS: Literature searching resulted in 11 selected studies, 9 selected for meta-analysis. Addition of bevacizumab showed significant better results in OS (HR 0.83, CI 95% 0.74–0.93; p = 0.002; I2 = 29%) and PFS (HR 0.62, 95% CI 0.51–0.75; p < 0.0001, I2 = 78%).
CONCLUSION: The addition of bevacizumab to chemotherapy resulted in better OS and PFS in untreated mCRC. Further studies are needed to confirm PFS benefit from the combination of bevacizumab and chemotherapy due to significant heterogeneity.
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Punt CJ, Kwakman JJ, Mol L, on-behalf-of-the-PLCRC-working-group, Roodhart J, Hendriks M, Speetjens F, van Iersel L, Trajkovic-Vidakovic M, Spierings L, Helgason H, Creemers GJ, de Groot JW, van Dodewaard-de Jong J, Los M, Koornstra R, Baars A, Koopman M, Vink G. Long-term safety data on S-1 administered after previous intolerance to capecitabine-containing systemic treatment for metastatic colorectal cancer. Clin Colorectal Cancer 2022; 21:229-235. [DOI: 10.1016/j.clcc.2022.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/08/2022] [Accepted: 02/24/2022] [Indexed: 12/27/2022]
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VEGF-A, VEGFR1 and VEGFR2 single nucleotide polymorphisms and outcomes from the AGITG MAX trial of capecitabine, bevacizumab and mitomycin C in metastatic colorectal cancer. Sci Rep 2022; 12:1238. [PMID: 35075138 PMCID: PMC8786898 DOI: 10.1038/s41598-021-03952-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/24/2021] [Indexed: 02/08/2023] Open
Abstract
The phase III MAX clinical trial randomised patients with metastatic colorectal cancer (mCRC) to receive first-line capecitabine chemotherapy alone or in combination with the anti-VEGF-A antibody bevacizumab (± mitomycin C). We utilised this cohort to examine whether single nucleotide polymorphisms (SNPs) in VEGF-A, VEGFR1, and VEGFR2 are predictive of efficacy outcomes with bevacizumab or the development of hypertension. Genomic DNA extracted from archival FFPE tissue for 325 patients (69% of the MAX trial population) was used to genotype 16 candidate SNPs in VEGF-A, VEGFR1, and VEGFR2, which were analysed for associations with efficacy outcomes and hypertension. The VEGF-A rs25648 ‘CC’ genotype was prognostic for improved PFS (HR 0.65, 95% CI 0.49 to 0.85; P = 0.002) and OS (HR 0.70, 95% CI 0.52 to 0.94; P = 0.019). The VEGF-A rs699947 ‘AA’ genotype was prognostic for shorter PFS (HR 1.32, 95% CI 1.002 to 1.74; P = 0.048). None of the analysed SNPs were predictive of bevacizumab efficacy outcomes. VEGFR2 rs11133360 ‘TT’ was associated with a lower risk of grade ≥ 3 hypertension (P = 0.028). SNPs in VEGF-A, VEGFR1 and VEGFR2 did not predict bevacizumab benefit. However, VEGF-A rs25648 and rs699947 were identified as novel prognostic biomarkers and VEGFR2 rs11133360 was associated with less grade ≥ 3 hypertension.
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Yamada Y, Yoshimatsu K, Yokomizo H, Okayama S, Satake M, Ida A, Maeda H, Shiozawa S. Capecitabine Plus Bevacizumab as First-Line Therapy for Patients with Metastatic Colorectal Cancer and Poor Performance Status. J NIPPON MED SCH 2021; 88:496-499. [PMID: 32999176 DOI: 10.1272/jnms.jnms.2021_88-415] [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: 11/19/2022]
Abstract
BACKGROUND The benefit of chemotherapy for patients with metastatic colorectal cancer has not been established. METHODS We retrospectively evaluated the effectiveness of chemotherapy with capecitabine and bevacizumab for patients with a performance status (PS) of 3. RESULTS Seven patients were included; median age was 82 years (range, 65-91 years). Response was not ascertained; however, the disease control rate was 83.3%. Median PFS and OS were 10.0 and 25.8 months, respectively. Hand-foot syndrome was the most common toxicity observed (3 patients; 42.9%). Grade 3 toxicity was observed in 1 patient with proteinuria and 1 with hypertension. CONCLUSION Chemotherapy using capecitabine and bevacizumab appeared to improve OFS and OS for patients with poor PS. However, care must be taken not to impose unnecessary burdens on patients with poor PS.
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Affiliation(s)
- Yasufumi Yamada
- Department of Surgery, Tokyo Women's Medical University, Medical Center East
| | - Kazuhiko Yoshimatsu
- Department of Surgery, Tokyo Women's Medical University, Medical Center East
| | - Hajime Yokomizo
- Department of Surgery, Tokyo Women's Medical University, Medical Center East
| | - Sachiyo Okayama
- Department of Surgery, Tokyo Women's Medical University, Medical Center East
| | - Masaya Satake
- Department of Surgery, Tokyo Women's Medical University, Medical Center East
| | - Arika Ida
- Department of Surgery, Tokyo Women's Medical University, Medical Center East
| | - Hiroyuki Maeda
- Department of Surgery, Tokyo Women's Medical University, Medical Center East
| | - Shunichi Shiozawa
- Department of Surgery, Tokyo Women's Medical University, Medical Center East
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Yin G, Zhao L. Risk of hypertension with anti-VEGF monoclonal antibodies in cancer patients: a systematic review and meta-analysis of 105 phase II/III randomized controlled trials. J Chemother 2021; 34:221-234. [PMID: 34229563 DOI: 10.1080/1120009x.2021.1947022] [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: 01/15/2023]
Abstract
We performed a meta-analysis to fully investigate the hypertension of anti-VEGF mAbs in cancer patients. Databases were searched for randomized controlled trials (RCTs) treated with anti-VEGF mAbs till January 2021. The relevant RCTs in cancer patients treated with anti-VEGF mAbs were retrieved and the systematic evaluation was conducted. One hundred and five RCTs and 65358 patients were included. Our study suggests that anti-VEGF mAbs significantly increased the risks of all-grade (RR, 3.22; 95%CI, 2.83-3.65; p < 0.00001; I2=71%) and high-grade (RR, 6.15; 95%CI, 5.58-6.78; p < 0.00001; I2=48%) hypertension in cancer patients. Those risks may be dependent on drug type. Icrucumab did not association with an increased risk of hypertension. The RR of hypertension did not vary significantly according to the type of cancer, line of therapy, and treatment duration. The available data suggested that the use of anti-VEGF mAbs were associated with a significantly increased risk of hypertension.
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Affiliation(s)
- Gang Yin
- Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, P.R. China.,Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of pharmacy, Chengdu University, Chengdu, Sichuan, P.R. China
| | - Ling Zhao
- Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, P.R. China
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Colorectal Cancer: From Genetic Landscape to Targeted Therapy. JOURNAL OF ONCOLOGY 2021; 2021:9918116. [PMID: 34326875 PMCID: PMC8277501 DOI: 10.1155/2021/9918116] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/25/2021] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer type and the second cause of death worldwide. The advancement in understanding molecular pathways involved in CRC has led to new classifications based on the molecular characteristics of each tumor and also improved CRC management through the integration of targeted therapy into clinical practice. In this review, we will present the main molecular pathways involved in CRC carcinogenesis, the molecular classifications. The anti-VEGF and anti-EGFR therapies currently used in CRC treatment and those under clinical investigation will also be outlined, as well as the mechanisms of primary and acquired resistance to anti-EGFR monoclonal antibodies (cetuximab and panitumumab). Targeted therapy has led to great improvement in the treatment of metastatic CRC. However, there has been variability in CRC treatment outcomes due to molecular heterogeneity in colorectal tumors, which underscores the need for identifying prognostic and predictive biomarkers for CRC-targeted drugs.
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Yin J, Dawood S, Cohen R, Meyers J, Zalcberg J, Yoshino T, Seymour M, Maughan T, Saltz L, Van Cutsem E, Venook A, Schmoll HJ, Goldberg R, Hoff P, Hecht JR, Hurwitz H, Punt C, Diaz Rubio E, Koopman M, Cremolini C, Heinemann V, Tournigard C, Bokemeyer C, Fuchs C, Tebbutt N, Souglakos J, Doulliard JY, Kabbinavar F, Chibaudel B, de Gramont A, Shi Q, Grothey A, Adams R. Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis. Ther Adv Med Oncol 2021; 13:17588359211020547. [PMID: 34262614 PMCID: PMC8252342 DOI: 10.1177/17588359211020547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 05/05/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). DESIGN Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. RESULTS Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland (p = 0.0034 and p < 0.001, respectively), with median difference of 3-4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients (p < 0.001). CONCLUSIONS Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.
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Affiliation(s)
- Jun Yin
- Department of Health Sciences Research, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USA
| | - Shaheenah Dawood
- Mediclinic City Hospital: North Wing, Dubai Health Care City, Dubai UAE
| | - Romain Cohen
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Jeff Meyers
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - John Zalcberg
- School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | | | - Tim Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, UK
| | - Leonard Saltz
- Memory Sloan Kettering Cancer Center, New York, NY, USA
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - Alan Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA, USA
| | | | - Richard Goldberg
- Department of Oncology, West Virginia University, Morgantown, WV, USA
| | - Paulo Hoff
- Centro de Oncologia de Brasilia do Sirio Libanes: Unidade Lago Sul, Siro Libanes, Brazil
| | - J. Randolph Hecht
- Ronald Reagan UCLA Medical Center, UCLS Medical Center, Santa Monica, CA, USA
| | | | - Cornelis Punt
- Department of Medical Oncology, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Volker Heinemann
- Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany
| | | | - Carsten Bokemeyer
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Niall Tebbutt
- Sydney Medical School, University of Sydney, Sydney, Australia
| | | | | | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Qian Shi
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | | | - Richard Adams
- Cardiff University and Velindre Cancer Center, Cardiff, UK
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Selection of Oral Therapeutics in China for the Treatment of Colorectal Cancer. Curr Treat Options Oncol 2021; 22:55. [PMID: 34097129 DOI: 10.1007/s11864-021-00852-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2021] [Indexed: 12/24/2022]
Abstract
OPINION STATEMENT Intravenous administration of fluoropyrimidine-based chemotherapy has been the backbone of treatment in colorectal cancer (CRC) for decades. The availability of oral capecitabine has improved the tolerability and simplified combination schedules. In addition to capecitabine, several other oral drugs have proven efficacy, particularly in palliative treatment lines. Clinical guidelines describe several available third-line treatment options for metastatic CRC (mCRC), but few insights are provided to guide the selection and sequence. In this review, we describe the available evidence and most recent data concerning oral drugs with proven efficacy in CRC, including antiangiogenetic tyrosine kinase inhibitors (VEGFR TKIs), inhibitors blocking EGFR/Raf/MEK/ERK signaling pathway and modified fluoropyrimidine, and share recommendations and insights on selecting third-line oral therapies for mCRC in China. In general, third-line treatment options for mCRC are mainly regorafenib, fruquintinib, and chemo/targeted therapy reintroduction, while FTD/TPI was rarely used in China probably due to poor accessibility. Fruquintinib is preferred in patients with poor performance status (PS), elder age, and severe organ dysfunction, compared to regorafenib. New drugs of clinical trials were more recommended for the patients with BRAF mutant tumor, and those with good previous treatment efficacy tended to be recommended for chemo/targeted therapy reintroduction. The management of mCRC is evolving, and it must be emphasized that the consideration and recommendations presented here reflect current treatment practices in China and thus might change according to new clinical data as well as the availability of new oral drugs.
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Kristin E, Endarti D, Khoe LC, Taroeno-Hariadi KW, Trijayanti C, Armansyah A, Sastroasmoro S. Economic Evaluation of Adding Bevacizumab to Chemotherapy for Metastatic Colorectal Cancer (mCRC) Patients in Indonesia. Asian Pac J Cancer Prev 2021; 22:1921-1926. [PMID: 34181352 PMCID: PMC8418847 DOI: 10.31557/apjcp.2021.22.6.1921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/19/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Since 2016, bevacizumab has been widely used to treat metastatic colorectal cancer (mCRC) in Indonesia. Nevertheless, the high cost of bevacizumab has raised the question of whether the therapy is considered cost-effective and should be included in the national health insurance system. This study aimed to assess the cost-effectiveness of bevacizumab plus chemotherapy versus chemotherapy alone for the treatment of mCRC patients. METHODS A Markov model was applied using the perspective of the Indonesian healthcare system to assess cost-effectiveness. The health outcomes were expressed in terms of quality-adjusted life years (QALY) using the validated EuroQoL-5D-5L instrument. Data for medical costs were collected from hospital billings in four hospitals located in three different cities in Indonesia. Meanwhile, data for utility were obtained from interviewing 90 patients who came to the hospital. We compared those mCRC patients who received chemotherapy alone either with FOLFOX or FOLFIRI, versus patients who received the addition of bevacizumab. RESULTS With the perspective of societal, the incremental cost-effectiveness ratio (ICER) of adding bevacizumab was USD 49,312 per QALY gained using secondary data and USD 28,446 per QALY using real world data. CONCLUSION Using either a healthcare or societal perspective, the addition of bevacizumab for mCRC treatment was considered not cost-effective.
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Affiliation(s)
- Erna Kristin
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia.
| | - Dwi Endarti
- Department of Pharmaceutics, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia.
| | - Levina Chandra Khoe
- Department of Community Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
| | - Kartika Widayati Taroeno-Hariadi
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia.
| | | | - Armansyah Armansyah
- Center of Financing and Health Insurance, Ministry of Health, Government of Indonesia, Indonesia.
| | - Sudigdo Sastroasmoro
- Department of Pediatrics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
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Pouya FD, Rasmi Y, Camci IY, Tutar Y, Nemati M. Performance of capecitabine in novel combination therapies in colorectal cancer. J Chemother 2021; 33:375-389. [PMID: 34019782 DOI: 10.1080/1120009x.2021.1920247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Colorectal cancer is one of the most common cancers throughout the world, and no definitive cure has ever been found. Perhaps a new insight into the effectiveness of chemotherapy drugs could help better treat patients. Targeted therapies have significantly improved the median overall survival of colorectal cancer patients. One of the standard chemotherapy regimens used for colorectal cancer is capecitabine, which is important in monotherapy and combination therapies. Capecitabine, with other chemotherapeutic agents (irinotecan, oxaliplatin, perifosine, 17-allylamino-17-demethoxygeldanamycin, aspirin, celecoxib, statins, quinacrine, inositol hexaphosphate and inositol, cystine/theanine, curcumin, and isorhamnetin), and biological ones (antibodies) plays an important role in the inhibition of some signaling pathways, increasing survival, reducing tumor growth and side effects of capecitabine. However, some drugs, such as proton pump inhibitors, are negatively related to capecitabine; therefore, the purpose of this work is to review and discuss the performance of capecitabine combination therapies in colorectal cancer.
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Affiliation(s)
- Fahima Danesh Pouya
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Irem Yalim Camci
- Department of Molecular Biology and Genetics, Faculty of Science, Gebze Technical University, Kocaeli, Turkey
| | - Yusuf Tutar
- Division of Biochemistry, Department of Basic Pharmaceutical Sciences, Hamidiye Faculty of Pharmacy, University of Health Sciences, Turkey Istanbul
| | - Mohadeseh Nemati
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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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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Gulhati P, Yin J, Pederson L, Schmoll HJ, Hoff P, Douillard JY, Hecht JR, Tournigand C, Tebbut N, Chibaudel B, Gramont AD, Shi Q, Overman MJ. Threshold Change in CEA as a Predictor of Non-Progression to First-Line Systemic Therapy in Metastatic Colorectal Cancer Patients With Elevated CEA. J Natl Cancer Inst 2021; 112:1127-1136. [PMID: 32191317 DOI: 10.1093/jnci/djaa020] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 12/17/2019] [Accepted: 01/28/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Carcinoembryonic antigen (CEA) levels are used in conjunction with imaging to monitor response to systemic therapy in metastatic colorectal cancer (mCRC). We sought to identify a threshold for CEA change from baseline to predict progressive disease (PD) in mCRC patients receiving first-line therapy. METHODS Patients from trials collected in the ARCAD database were included if baseline CEA was at least 10 ng/mL and repeat CEA was available within 14 days of first restaging scan. Optimal cutoffs for CEA change were identified by receiver operating characteristic analysis. Prediction performance of cutoffs was evaluated by sensitivity, specificity, and negative predictive value. Analyses were conducted by treatment class: chemotherapy alone, chemotherapy with anti-VEGF antibody, and chemotherapy with anti-EGFR antibody. RESULTS A total of 2643 mCRC patients treated with systemic therapy were included. Median percent change of CEA from baseline to first restaging for patients with complete response, partial response, or stable disease (non-PD) and PD was -53.1% and +23.6% for chemotherapy alone (n = 957) and -71.7% and -45.3% for chemotherapy with anti-VEGF antibody (n = 1355). The optimal area under the curve cutoff for differentiating PD from non-PD on first restaging was -7.5% for chemotherapy alone and -62.0% for chemotherapy with anti-VEGF antibody; chemotherapy alone, adjusted odds ratio = 6.51 (95% CI = 3.31 to 12.83, P < .001), chemotherapy with anti-VEGF antibody, adjusted odds ratio = 3.45 (95% CI = 1.93 to 6.18, P < .001). A 99% negative predictive value clinical cutoff for prediction of non-PD would avoid CT scan at first restaging in 21.0% of chemotherapy alone and 16.2% of chemotherapy with anti-VEGF antibody-treated patients. Among patients with stable disease on first restaging, those with decreased CEA from baseline had statistically significantly improved progression-free and overall survival. CONCLUSIONS Change in CEA from baseline to first restaging can accurately predict non-progression and correlates with long-term outcomes in patients receiving systemic chemotherapy.
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Affiliation(s)
- Pat Gulhati
- Department of Medical Oncology, Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA
| | - Jun Yin
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Levi Pederson
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | | | - Paulo Hoff
- Centro de Oncologia de Brasilia do Sirio Libanes-Unidade Lago Sul, Sao Paulo, Brazil
| | - Jean-Yves Douillard
- Integrated Centres for Oncology, Department of Medical Oncology, St-Herblain, France
| | - J Randolph Hecht
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | | | - Niall Tebbut
- Department of Oncology, Olivia Newton John Cancer Research Institute, Heidelberg, VIC, Australia
| | | | | | - Qian Shi
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Michael James Overman
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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46
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Mahmood RD, Shaw D, Descamps T, Zhou C, Morgan RD, Mullamitha S, Saunders M, Mescallado N, Backen A, Morris K, Little RA, Cheung S, Watson Y, O'Connor JPB, Jackson A, Parker GJM, Dive C, Jayson GC. Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study. BMC Cancer 2021; 21:354. [PMID: 33794823 PMCID: PMC8017714 DOI: 10.1186/s12885-021-08097-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 03/24/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. METHODS A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). RESULTS Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). CONCLUSIONS In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.
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Affiliation(s)
- Reem D Mahmood
- Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
| | - Danielle Shaw
- The Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK
| | - Tine Descamps
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, UK
| | - Cong Zhou
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, UK
| | - Robert D Morgan
- Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK
- Division of Cancer Sciences, School of Medicine, University of Manchester, Manchester, UK
| | - Saifee Mullamitha
- Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK
| | - Mark Saunders
- Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK
| | - Nerissa Mescallado
- Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK
| | - Alison Backen
- Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK
- Division of Cancer Sciences, School of Medicine, University of Manchester, Manchester, UK
| | - Karen Morris
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, UK
| | - Ross A Little
- Division of Cancer Sciences, School of Medicine, University of Manchester, Manchester, UK
| | - Susan Cheung
- Division of Cancer Sciences, School of Medicine, University of Manchester, Manchester, UK
| | - Yvonne Watson
- Division of Cancer Sciences, School of Medicine, University of Manchester, Manchester, UK
| | - James P B O'Connor
- Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK
- Division of Cancer Sciences, School of Medicine, University of Manchester, Manchester, UK
| | - Alan Jackson
- Division of Informatics, Imaging and Data Sciences, School of Health Sciences, University of Manchester, Manchester, UK
| | - Geoff J M Parker
- Division of Informatics, Imaging and Data Sciences, School of Health Sciences, University of Manchester, Manchester, UK
- Bioxydyn Limited, Manchester, UK
- Department of Computer Science, Centre for Medical Image Computing, University College London, London, UK
| | - Caroline Dive
- Cancer Research UK Manchester Institute Cancer Biomarker Centre, University of Manchester, Alderley Park, Macclesfield, UK
| | - Gordon C Jayson
- Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK
- Division of Cancer Sciences, School of Medicine, University of Manchester, Manchester, UK
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47
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Angiogenesis Inhibitors for Colorectal Cancer. A Review of the Clinical Data. Cancers (Basel) 2021; 13:cancers13051031. [PMID: 33804554 PMCID: PMC7957514 DOI: 10.3390/cancers13051031] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 02/21/2021] [Indexed: 12/24/2022] Open
Abstract
Since the late 1990s, therapy for metastatic colorectal cancer (mCRC) has changed considerably, and the combination of doublet or triplet chemotherapy and a targeted agent are now routinely used. The targeting of angiogenesis, the development of new blood vessels, represents a key element in the overall treatment strategy. Since the approval in 2004 of the first anti-angiogenetic drug, multiple agents have been approved and others are currently under investigation. We present an overview of the recent literature on approved systemic treatment of mCRC, with a focus on anti-angiogenic drugs, and current treatment approaches, and elaborate on the future role of angiogenesis in colorectal cancer as seen from a clinical perspective. The treatment of mCRC, in general, has changed from "one strategy fits all" to a more personalized approach. This is, however, not entirely the case for anti-angiogenetic treatments, partly due to a lack of validated biomarkers. The anti-angiogenetic standard treatment at the present primarily includes monoclonal antibodies. The therapeutic field of angiogenesis, however, has received increased interest after the introduction of newer combinations. These approaches will likely change the current treatment strategy, once again, to the overall benefit of patients.
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48
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Rodriguez A, Esposito F, Oliveres H, Torres F, Maurel J. Are Quality of Randomized Clinical Trials and ESMO-Magnitude of Clinical Benefit Scale Two Sides of the Same Coin, to Grade Recommendations for Drug Approval? J Clin Med 2021; 10:746. [PMID: 33668473 PMCID: PMC7918206 DOI: 10.3390/jcm10040746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/06/2021] [Accepted: 02/11/2021] [Indexed: 12/20/2022] Open
Abstract
The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them are analyzed to support the recommendations. For this reason, there are different scales to quantify and evaluate the quality of RCTs and the magnitude of the clinical benefits of new drugs for treating solid tumors. In this review, we discuss the value of the progression-free survival (PFS) as an endpoint in RCTs and the concordance between it and the overall survival (OS) as a measure of the quality of clinical trial designs. We summarize and analyze the different scales to evaluate the clinical benefits of new drugs such as the The American Society of Clinical Oncology value framework (ASCO-VF-NHB16) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the concordance between them, focusing on metastatic colorectal cancer (mCRC). We propose several definitions that would help to evaluate the quality of RCT, the magnitude of clinical benefit and the appropriate approval of new drugs in oncology.
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Affiliation(s)
- Adela Rodriguez
- Department of Medical Oncology, Hospital Clinic of Barcelona,08036 Barcelona, Spain; (A.R.); (F.E.); (H.O.)
- Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Department of Medicine, University of Barcelona, 08036 Barcelona, Spain
- Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, 08036 Barcelona, Spain
| | - Francis Esposito
- Department of Medical Oncology, Hospital Clinic of Barcelona,08036 Barcelona, Spain; (A.R.); (F.E.); (H.O.)
- Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Department of Medicine, University of Barcelona, 08036 Barcelona, Spain
- Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, 08036 Barcelona, Spain
| | - Helena Oliveres
- Department of Medical Oncology, Hospital Clinic of Barcelona,08036 Barcelona, Spain; (A.R.); (F.E.); (H.O.)
- Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Department of Medicine, University of Barcelona, 08036 Barcelona, Spain
- Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, 08036 Barcelona, Spain
| | - Ferran Torres
- Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, 08036 Barcelona, Spain
| | - Joan Maurel
- Department of Medical Oncology, Hospital Clinic of Barcelona,08036 Barcelona, Spain; (A.R.); (F.E.); (H.O.)
- Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Department of Medicine, University of Barcelona, 08036 Barcelona, Spain
- Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, 08036 Barcelona, Spain
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Role of Vascular Endothelial Growth Factor (VEGF) in Human Embryo Implantation: Clinical Implications. Biomolecules 2021; 11:biom11020253. [PMID: 33578823 PMCID: PMC7916576 DOI: 10.3390/biom11020253] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor that plays a critical role in various physiological and pathological processes. VEGF also contributes to the process of embryo implantation by enhancing embryo development, improving endometrial receptivity, and facilitating the interactions between the developing embryo and the endometrium. There is a correlation between the alteration of VEGF expression and reproductive failure, including recurrent implantation failure (RIF) and recurrent miscarriage (RM). In order to clarify the role of VEGF in embryo implantation, we reviewed recent literature concerning the expression and function of VEGF in the reproductive system around the time of embryo implantation and we provide a summary of the findings reported so far. We also explored the effects and the possible underlying mechanisms of action of VEGF in embryo implantation.
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50
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Gaibar M, Galán M, Romero-Lorca A, Antón B, Malón D, Moreno A, Fernández-Santander A, Novillo A. Genetic Variants of ANGPT1, CD39, FGF2 and MMP9 Linked to Clinical Outcome of Bevacizumab Plus Chemotherapy for Metastatic Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22031381. [PMID: 33573134 PMCID: PMC7866547 DOI: 10.3390/ijms22031381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis pathway genes show substantial genetic variability causing inter-individual differences in responses to anti-angiogenic drugs. We examined 20 single nucleotide polymorphisms (SNPs) in 13 of these genes to predict tumour response and clinical outcome measured as progression free survival (PFS) and overall survival (OS) in 57 patients with metastatic colorectal cancer (mCRC) given bevacizumab plus chemotherapy. SNPs were detected (iPLEX® Assay) in genomic DNA extracted from formalin-fixed paraffin-embedded tumour specimens. The variant allele CD39 rs11188513 was associated with a good tumour response (p = 0.024). Patients homozygous for the wild-type allele FGF2 rs1960669 showed a median PFS of 10.95 months versus 5.44 months for those with at least one variant allele-A (HR 3.30; 95% CI: 1.52–7.14; p = 0.001). Patients homozygous for wild-type MMP9 rs2236416 and rs2274755 showed a median PFS of 9.48 months versus 6 and 6.62 months, respectively, for those with at least one variant allele (p = 0.022, p = 0.043, respectively). OS was also lengthened to 30.92 months (p = 0.034) in carriers of wild-type ANGPT1 rs2445365 versus 22.07 months for those carrying at least one variant allele-A. These gene variants were able to predict clinical outcome and tumour response in mCRC patients given bevacizumab-based therapy.
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Affiliation(s)
- María Gaibar
- Department of Health Sciences, Health Sciences Faculty, European University of Madrid, Villaviciosa de Odón, 28670 Madrid, Spain; (M.G.); (M.G.)
| | - Miguel Galán
- Department of Health Sciences, Health Sciences Faculty, European University of Madrid, Villaviciosa de Odón, 28670 Madrid, Spain; (M.G.); (M.G.)
| | - Alicia Romero-Lorca
- Department of Medicine, Health Sciences Faculty, Universidad Europea de Madrid, Villaviciosa de Odón, 28670 Madrid, Spain; (A.R.-L.); (A.F.-S.)
| | - Beatriz Antón
- Department of Oncology, University Hospital of Fuenlabrada, Fuenlabrada, 28942 Madrid, Spain; (B.A.); (D.M.)
| | - Diego Malón
- Department of Oncology, University Hospital of Fuenlabrada, Fuenlabrada, 28942 Madrid, Spain; (B.A.); (D.M.)
| | - Amalia Moreno
- Department of Pathological Anatomy, University Hospital of Fuenlabrada, Fuenlabrada, 28942 Madrid, Spain;
| | - Ana Fernández-Santander
- Department of Medicine, Health Sciences Faculty, Universidad Europea de Madrid, Villaviciosa de Odón, 28670 Madrid, Spain; (A.R.-L.); (A.F.-S.)
| | - Apolonia Novillo
- Department of Pre-Clinical Dentistry, Health Sciences Faculty, Universidad Europea de Madrid, Villaviciosa de Odón, 28670 Madrid, Spain
- Correspondence: ; Tel.: +34-912-115-393
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