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Kita K, Burdowski A. Recent clinical trials and optical control as a potential strategy to develop microtubule-targeting drugs in colorectal cancer management. World J Gastroenterol 2024; 30:1780-1790. [PMID: 38659489 PMCID: PMC11036503 DOI: 10.3748/wjg.v30.i13.1780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/08/2024] [Accepted: 03/19/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) has remained the second and the third leading cause of cancer-related death worldwide and in the United States, respectively. Although significant improvement in overall survival has been achieved, death in adult populations under the age of 55 appears to have increased in the past decades. Although new classes of therapeutic strategies such as immunotherapy have emerged, their application is very limited in CRC so far. Microtubule (MT) inhibitors such as taxanes, are not generally successful in CRC. There may be some way to make MT inhibitors work effectively in CRC. One potential advantage that we can take to treat CRC may be the combination of optical techniques coupled to an endoscope or other fiber optics-based devices. A combination of optical devices and photo-activatable drugs may allow us to locally target advanced CRC cells with highly potent MT-targeting drugs. In this Editorial review, we would like to discuss the potential of optogenetic approaches in CRC management.
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Affiliation(s)
- Katsuhiro Kita
- Department of Biology, St. Francis College, Brooklyn, NY 11201, United States
| | - Allen Burdowski
- Department of Biology, St. Francis College, Brooklyn, NY 11201, United States
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2
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Kok DE, van Duijnhoven FJ, Lubberman FJ, McKay JA, Lanen ASV, Winkels RM, Wesselink E, van Halteren HK, de Wilt JH, Ulrich CM, Ulvik A, Ueland PM, Kampman E. Intake and biomarkers of folate and folic acid as determinants of chemotherapy-induced toxicities in patients with colorectal cancer: a cohort study. Am J Clin Nutr 2024; 119:294-301. [PMID: 38070682 DOI: 10.1016/j.ajcnut.2023.11.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/10/2023] [Accepted: 11/28/2023] [Indexed: 12/25/2023] Open
Abstract
BACKGROUND Capecitabine is an oral chemotherapeutic drug showing antitumor activity through inhibition of thymidylate synthase, an enzyme involved in folate metabolism. There are concerns about the high intake of certain vitamins, and specifically folate, during chemotherapy with capecitabine. Whether folate or folic acid, the synthetic variant of the vitamin, impact treatment toxicity remains unclear. OBJECTIVE We studied associations between intake and biomarkers of folate as well as folic acid and toxicities in patients with colorectal cancer (CRC) receiving capecitabine. METHODS Within the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort, 290 patients with stage II to III CRC receiving capecitabine were identified. Dietary and supplemental intake of folate and folic acid were assessed at diagnosis and during chemotherapy using questionnaires (available for 280 patients). Plasma folate and folic acid levels were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and were available for 212 patients. Toxicities were defined as toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Associations of intake and biomarkers of folate and folic acid with toxicities were determined using Cox proportional hazards regression adjusted for age and sex. RESULTS In total, 153 (53%) patients experienced toxicities leading to modification of capecitabine treatment. Folate intake and plasma folate levels were not associated with risk of toxicities. However, use of folic acid-containing supplements during treatment (hazard ratio (HR) 1.81 and 95% confidence interval (CI) 1.15-2.85) and presence of folic acid in plasma at diagnosis (HR 2.09, 95% CI: 1.24, 3.52) and during treatment (HR 2.31, 95% CI: 1.29, 4.13) were associated with an increased risk of toxicities. CONCLUSIONS This study suggests a potential association between folic acid and capecitabine-induced toxicities, providing a rationale to study diet-drug interactions and raise further awareness of the use of dietary supplements during oncological treatment. CLINICAL TRIAL DETAILS This trial was registered at clinicaltrials.gov as NCT03191110.
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Affiliation(s)
- Dieuwertje E Kok
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.
| | - Fränzel Jb van Duijnhoven
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Floor Je Lubberman
- Department of Clinical Pharmacy, Hospital Gelderse Vallei, Ede, the Netherlands
| | - Jill A McKay
- Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
| | - Anne-Sophie van Lanen
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Renate M Winkels
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Evertine Wesselink
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Henk K van Halteren
- Department of Medical Oncology, Admiraal de Ruyter Hospital, Goes, the Netherlands
| | | | - Cornelia M Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, United States
| | | | | | - Ellen Kampman
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
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Li XJ, Nie P, Herdewijn P, Sun JG. Unlocking the synthetic approaches and clinical application of approved small-molecule drugs for gastrointestinal cancer treatment: A comprehensive exploration. Eur J Med Chem 2023; 262:115928. [PMID: 37944387 DOI: 10.1016/j.ejmech.2023.115928] [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: 10/15/2023] [Revised: 10/29/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023]
Abstract
Gastrointestinal (GI) cancers encompass a group of malignancies affecting the digestive system, including the stomach, esophagus, liver, colon, rectum and pancreas. These cancers represent a significant global health burden, necessitating effective treatment strategies. Small-molecule drugs have emerged as crucial therapeutic options in the fight against GI cancers due to their oral bioavailability, targeted mechanisms of action, and well-established safety profiles. The review then elucidates the clinical applications and synthetic methods of clinically approved small-molecule drugs for the treatment of GI cancer, shedding light on their mechanisms of action and their potential in mitigating GI cancer progression. The review also discusses future prospects and the evolving landscape of small-molecule drug development in GI oncology, highlighting the potential for personalized medicine. In summary, this review provides valuable insights into cutting-edge strategies for harnessing clinically approved small-molecule drugs to combat GI cancer effectively.
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Affiliation(s)
- Xiao-Jing Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Peng Nie
- Medicinal Chemistry, Rega Institute of Medical Research, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
| | - Piet Herdewijn
- Medicinal Chemistry, Rega Institute of Medical Research, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
| | - Jian-Gang Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
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Awada A, Boni V, Moreno V, Aftimos P, Kahatt C, Luepke-Estefan X, Siguero M, Fernandez-Teruel C, Cullell-Young M, Tabernero J. Antitumor activity of lurbinectedin in combination with oral capecitabine in patients with metastatic breast cancer. ESMO Open 2022; 7:100651. [PMID: 36455505 PMCID: PMC9808480 DOI: 10.1016/j.esmoop.2022.100651] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/25/2022] [Accepted: 10/31/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Preclinical studies showed a synergistic effect for 5-fluorouracil and lurbinectedin against solid tumors. This phase I trial evaluated a combination of capecitabine plus lurbinectedin in patients with selected advanced solid tumors. Results in patients with relapsed metastatic breast cancer (MBC) are described. PATIENTS AND METHODS Patients received capecitabine daily on day (D)1-D14 combined with lurbinectedin on D1, D8 or D1 every 3 weeks (q3w) intravenously, following a standard 3 + 3 escalation design and expansion at the recommended dose (RD). RESULTS Of the 81 enrolled patients, 28 had relapsed MBC: 20 with hormone receptor (HR)-positive tumors and 8 with triple-negative tumors; 3 treated in the D1,D8 schedule and 25 in the D1 schedule. The RD was capecitabine 1650 mg/m2 daily on D1-D14 plus lurbinectedin 2.2 mg/m2 on D1 q3w. Sixteen confirmed responses and two prolonged disease stabilizations (≥6 months) were observed [overall response rate (ORR)/clinical benefit rate (CBR) = 57%/64% at all dose levels; 47%/60% at the RD]. Twelve responses and both prolonged stabilizations occurred in HR-positive tumors (ORR/CBR = 60%/70% at all dose levels, 56%/78% at the RD). Four responses were found in triple-negative tumors (ORR and CBR = 50% at all dose levels; 33% at the RD). Myelotoxicity was reversible and manageable at the RD; most non-hematological toxicities were mild/moderate. No episodes of febrile neutropenia or severe palmar-plantar erythrodysesthesia syndrome occurred. No major pharmacokinetic drug-drug interaction was found between lurbinectedin, capecitabine or capecitabine metabolites. CONCLUSIONS The capecitabine/lurbinectedin combination showed encouraging clinical activity in relapsed MBC, especially in HR-positive tumors. Toxicity was manageable at the RD. Further development is warranted in relapsed MBC.
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Affiliation(s)
- A.H. Awada
- Oncology Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - V. Boni
- START Madrid—HM CIOCC, Hospital Madrid Norte Sanchinarro, Madrid, Spain
| | - V. Moreno
- START Madrid—FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
| | - P. Aftimos
- Oncology Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - C. Kahatt
- PharmaMar, Colmenar Viejo, Madrid, Spain
| | | | - M. Siguero
- PharmaMar, Colmenar Viejo, Madrid, Spain
| | | | | | - J. Tabernero
- Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quirón, UVic-UCC, Barcelona, Spain,Correspondence to: Dr Josep Tabernero, Vall d’Hebron University Hospital and Institute of Oncology (VHIO), Passeig de la Vall d’Hebron, 119, 08035 Barcelona, Spain. Tel: +34-93-274-60-85. @TaberneroJosep
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Study on Huangqi Bazhen Decoction on Relieving Chemotherapy Intestinal Mucositis in Capecitabine Gavage Mice. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:3826080. [PMID: 36247864 PMCID: PMC9534644 DOI: 10.1155/2022/3826080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/18/2022] [Accepted: 09/03/2022] [Indexed: 01/26/2023]
Abstract
In order to provide evidence for clinical application, the therapeutic effect and mechanism of Huangqi Bazhen decoction on chemotherapeutic intestinal mucositis induced by capecitabine in mice are investigated. In this paper, the mice are divided into different groups and given capecitabine intragastric administration or treatment drugs. Morphological features of intestinal injury, including villus height shortening, crypt destruction, and apoptosis, are reversed. The experimental results show that Huangqi Bazhen decoction can significantly reduce weight loss and diarrhea during capecitabine treatment. It is also found that GSH-Px and T-SOD can be improved while MDA, IL-1β, and TNF-α are reduced significantly.
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Clinical Pharmacokinetics of Capecitabine and its Metabolites in Colorectal cancer patients. Saudi Pharm J 2022; 30:527-531. [PMID: 35693432 PMCID: PMC9177445 DOI: 10.1016/j.jsps.2022.02.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 02/27/2022] [Indexed: 11/24/2022] Open
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Liu L, Brown EN, Abu-Shahin FI. Capecitabine-induced leukoencephalopathy in a patient with triple-negative breast cancer: A case report and review of the literature. J Oncol Pharm Pract 2021; 28:703-709. [PMID: 34791927 DOI: 10.1177/10781552211056856] [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] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Capecitabine is an orally administered prodrug that converts preferentially to 5-fluorouracil within tumors, resulting in enhanced concentrations of 5-fluorouracil in tumor tissue. The use of capecitabine has shown efficacy in the metastatic setting for breast cancer, and more recently, efficacy as adjuvant therapy for triple-negative breast cancer (TNBC). Capecitabine has been shown to be well tolerated with minimal side effects, but the incidence of leukoencephalopathy is rare with a risk of less than one percent. CASE REPORT We report on a 34-year-old female patient with left TNBC, moderately differentiated, stage IIB that experienced symptoms of neurotoxicity following initiation of adjuvant chemotherapy with capecitabine. MANAGEMENT AND OUTCOME Naranjo Algorithm Assessment score of nine indicated patient had drug-induced leukoencephalopathy leading to discontinuation of capecitabine and resolution of the neurotoxicity symptoms. DISCUSSION Early detection of capecitabine-induced neurotoxicity by magnetic resonance imaging is crucial as symptoms may be reversible to the condition that capecitabine is immediately discontinued.
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Affiliation(s)
- Li Liu
- Rangel College of Pharmacy, 2655Texas A&M University, Kingsville, TX, USA
| | - Erika N Brown
- Pharmacy Department, 23532 Houston Methodist Willowbrook Hospital, Houston, TX, USA
| | - Fadi I Abu-Shahin
- Hematology/Oncology Department, 23532Houston Methodist Hospital, Houston, TX, USA
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Alqahtani S, Alfarhan A, Alsultan A, Alsarhani E, Alsubaie A, Asiri Y. Assessment of Micafungin Dosage Regimens in Patients with Cancer Using Pharmacokinetic/Pharmacodynamic Modeling and Monte Carlo Simulation. Antibiotics (Basel) 2021; 10:antibiotics10111363. [PMID: 34827301 PMCID: PMC8615109 DOI: 10.3390/antibiotics10111363] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/03/2021] [Accepted: 11/06/2021] [Indexed: 11/18/2022] Open
Abstract
Micafungin is widely used for invasive candidiasis, especially in critically ill patients and those with cancer, and for empirical antifungal therapy in patients with neutropenic fever. This is the first study to investigate the pharmacokinetics and disposition parameters of micafungin in patients with cancer. In this observational pharmacokinetic study, blood samples were collected and analyzed using high-performance liquid chromatography. Pharmacokinetic parameters were estimated using Monolix 4.4 software. The plasma micafungin concentrations were measured in a total of 133 samples from 19 patients. In the final two-compartment model with linear elimination, the estimated micafungin clearance (CL) was significantly higher in patients with cancer than in those without cancer (1.2 vs. 0.6 L/h, p = 0.012), whereas other parameters did not significantly differ between the two groups. Aspartate and alanine transaminases and body weight significantly influenced micafungin CL in patients, with and without cancer. Overall, the probability of target attainment increased with increasing doses and decreased with higher MICs in both groups. In simulations, the patients without cancer achieved higher pharmacokinetic/pharmacodynamic targets with a 90% probability for all simulated doses, compared to the patients with cancer. Micafungin demonstrated dose-proportional linear pharmacokinetics in both the patients with and those without cancer. The estimated micafungin CL was significantly higher in patients with cancer, suggesting a need for increased dosage, especially for Candida spp. with high MICs, in these patients. Further studies should assess the efficacy and optimum dosage of micafungin for the treatment and prevention of febrile neutropenia (FN) in patients with cancer.
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Affiliation(s)
- Saeed Alqahtani
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.A.); (A.A.); (E.A.); (A.A.); (Y.A.)
- Clinical Pharmacokinetics and Pharmacodynamics Unit, King Saud University Medical City, Riyadh 11451, Saudi Arabia
- Correspondence:
| | - Asma Alfarhan
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.A.); (A.A.); (E.A.); (A.A.); (Y.A.)
- Clinical Pharmacokinetics and Pharmacodynamics Unit, King Saud University Medical City, Riyadh 11451, Saudi Arabia
| | - Abdullah Alsultan
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.A.); (A.A.); (E.A.); (A.A.); (Y.A.)
- Clinical Pharmacokinetics and Pharmacodynamics Unit, King Saud University Medical City, Riyadh 11451, Saudi Arabia
| | - Emad Alsarhani
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.A.); (A.A.); (E.A.); (A.A.); (Y.A.)
- Clinical Pharmacokinetics and Pharmacodynamics Unit, King Saud University Medical City, Riyadh 11451, Saudi Arabia
| | - Abdulaziz Alsubaie
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.A.); (A.A.); (E.A.); (A.A.); (Y.A.)
- Clinical Pharmacokinetics and Pharmacodynamics Unit, King Saud University Medical City, Riyadh 11451, Saudi Arabia
| | - Yousif Asiri
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (A.A.); (A.A.); (E.A.); (A.A.); (Y.A.)
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Aarnoutse R, Ziemons J, de Vos-Geelen J, Valkenburg-van Iersel L, Wildeboer ACL, Vievermans A, Creemers GJM, Baars A, Vestjens HJHMJ, Le GN, Barnett DJM, Rensen SS, Penders J, Smidt ML. The Role of Intestinal Microbiota in Metastatic Colorectal Cancer Patients Treated With Capecitabine. Clin Colorectal Cancer 2021; 21:e87-e97. [PMID: 34801414 DOI: 10.1016/j.clcc.2021.10.004] [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] [Received: 05/07/2021] [Revised: 09/29/2021] [Accepted: 10/13/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Previous pre-clinical research has indicated that the intestinal microbiota can potentiate anti-tumour efficacy of capecitabine and that capecitabine treatment impacts intestinal microbiota composition and diversity. Using a longitudinal design, this study explores the associations between the intestinal microbiota and treatment response in patients with metastatic colorectal cancer (mCRC) during capecitabine treatment. PATIENTS AND METHODS Patients with mCRC treated with capecitabine were prospectively enrolled in a multicentre cohort study. Patients collected a faecal sample and completed a questionnaire before, during, and after three cycles of capecitabine. Several clinical characteristics, including tumour response, toxicity and antibiotic use were recorded. Intestinal microbiota were analysed by amplicon sequencing of the 16S rRNA V4 gene-region. RESULTS Thirty-three patients were included. After three cycles of capecitabine, six patients (18%) achieved a partial response, 25 (76%) showed stable disease, and one (3%) experienced progressive disease. Of the 90 faecal samples were collected. Microbial diversity (α-diversity), community structure (β-diversity), and bacterial abundance on phylum and genus level were not significantly different between responders and non-responders and were not significantly affected by three cycles of capecitabine. CONCLUSION This is the first clinical study with longitudinal intestinal microbiota sampling in mCRC patients that explores the role of the intestinal microbiota during treatment with capecitabine. Intestinal microbiota composition and diversity before, during, and after three cycles of capecitabine were not associated with response in this study population. Capecitabine did not induce significant changes in the microbiota composition and diversity during the treatment period. Individual effects of antibiotics during capecitabine treatment were observed.
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Affiliation(s)
- Romy Aarnoutse
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Janine Ziemons
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Judith de Vos-Geelen
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Liselot Valkenburg-van Iersel
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Aurelia C L Wildeboer
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Anne Vievermans
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | | | - Arnold Baars
- Department of Medical Oncology, Hospital Gelderse Vallei, Ede, The Netherlands
| | | | - Giang N Le
- Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - David J M Barnett
- Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, The Netherlands; Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands
| | - Sander S Rensen
- Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands; NUTRIM - School of Nutrition and Translational research In Metabolism, Maastricht University, Maastricht, The Netherlands
| | - John Penders
- Department of Medical Microbiology, Maastricht University Medical Centre, Maastricht, The Netherlands; NUTRIM - School of Nutrition and Translational research In Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Marjolein L Smidt
- GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands.
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10
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Comparative study of low dose of capecitabine versus standard dose in metastatic breast cancer: Efficacy and safety. FORUM OF CLINICAL ONCOLOGY 2021. [DOI: 10.2478/fco-2019-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Background
A lower dose of capecitabine revealed better toxicity profiles and comparable efficacy in treatment of metastatic breast cancer (MBC). We aimed to evaluate the efficacy and toxicity of lower dose of capecitabine in comparison with the standard dose.
Patients and methods
Patients were enrolled in two groups. Group 1 included 21 patients who received the standard dose of capecitabine (1250 mg/m2 twice daily [BID] for 14 days), while the patients in group 2 (19 patients) received lower dose of capecitabine (850 mg/m2 BID for 14 days) every 3 weeks.
Results
In group 1, dose reduction was reported in 12 (57.1%) patients versus 1 patient in group 2 (5.3%; P = 0.0005). Patients in group 1 reported higher toxicity rates without any significant difference between the groups. The median duration of response was 17 weeks in group 1, while it was 19 weeks in group 2. Disease progression was recorded in 10 (47.6%) patients in group 1 versus 8 (42.1%) patients in group 2 (P = 0.81). The mean time to progression was 8.16 ± 0.63 months and the median was 10.1 months in group 1, while the mean was 8.98 ± 0.75 months and the median was 10 months in group 2 (P = 0.66). The overall survival had a mean of 11.94 ± 0.754 and 11.24 ± 0.665 months, while the median was 13.1 and 13 months in groups 1 and 2, respectively (P = 0.9).
Conclusion
A lower dose of capecitabine provides MBC patients with an active therapy that can be continued for prolonged periods to achieve long-term disease control without compromising its antitumor activity.
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11
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Scrutinizing the therapeutic and diagnostic potential of nanotechnology in thyroid cancer: Edifying drug targeting by nano-oncotherapeutics. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2020.102221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Fedele P, Sanna V, Fancellu A, Marino A, Calvani N, Cinieri S. De-escalating cancer treatments during COVID 19 pandemic: Is metronomic chemotherapy a reasonable option? Crit Rev Oncol Hematol 2021; 157:103148. [PMID: 33254036 PMCID: PMC7672334 DOI: 10.1016/j.critrevonc.2020.103148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 10/24/2020] [Accepted: 10/29/2020] [Indexed: 02/08/2023] Open
Abstract
COVID 19 pandemic represents an emergency for public health services and containment measures to reduce the risk of infection have been promptly activated worldwide. The healthcare systems reorganization has had a major impact on the management of cancer patients who are considered at high risk of infection. Recommendations and guidelines on how to manage cancer patients during COVID 19 pandemic have been published. Oral administration of chemotherapy is recommended to limit the access of cancer patients to hospital facilities and in some cases to guarantee the continuum of care. Low-dose metronomic administration of chemotherapy with different drugs and schedules has emerged in the last years as a possible alternative to conventional chemotherapy, due to its promising tumor control rates and excellent safety profiles. Moreover, given that many metronomic schedules use the oral route administration, it could represent a therapeutic strategy to ensure continuum of cancer care during COVID 19 pandemic. In this review we have selected all the clinical studies that have used the metronomic strategy, especially with oral drugs, in order to identify the subgroups of cancer patients who can benefit most from a metronomic approach even during COVID 19 pandemic.
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Affiliation(s)
- Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, Francavilla Fontana (Br), Italy.
| | - Valeria Sanna
- Medical Oncology, Hospital of Sassari, Sassari, Italy
| | - Alessandro Fancellu
- Department of Medical, Surgical and Experimental Sciences, Unit of General Surgery, University of Sassari, Sassari, Italy
| | - Antonella Marino
- Medical Oncology & Breast Unit, Antonio Perrino Hospital, Brindisi, Italy
| | - Nicola Calvani
- Medical Oncology & Breast Unit, Antonio Perrino Hospital, Brindisi, Italy
| | - Saverio Cinieri
- Medical Oncology & Breast Unit, Antonio Perrino Hospital, Brindisi, Italy
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Pan DC, Krishnan V, Salinas AK, Kim J, Sun T, Ravid S, Peng K, Wu D, Nurunnabi M, Nelson JA, Niziolek Z, Guo J, Mitragotri S. Hyaluronic acid-doxorubicin nanoparticles for targeted treatment of colorectal cancer. Bioeng Transl Med 2021; 6:e10166. [PMID: 33532580 PMCID: PMC7823125 DOI: 10.1002/btm2.10166] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/04/2020] [Accepted: 05/09/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer, common in both men and women, occurs when tumors form in the linings of the colon. Common treatments of colorectal cancer include surgery, chemotherapy, and radiation therapy; however, many colorectal cancer treatments often damage healthy tissues and cells, inducing severe side effects. Conventional chemotherapeutic agents such as doxorubicin (Dox) can be potentially used for the treatment of colorectal cancer; however, they suffer from limited targeting and lack of selectivity. Here, we report that doxorubicin complexed to hyaluronic acid (HA) (HA-Dox) exhibits an unusual behavior of high accumulation in the intestines for at least 24 hr when injected intravenously. Intravenous administrations of HA-Dox effectively preserved the mucosal epithelial intestinal integrity in a chemical induced colon cancer model in mice. Moreover, treatment with HA-Dox decreased the expression of intestinal apoptotic and inflammatory markers. The results suggest that HA-Dox could effectively inhibit the development of colorectal cancer in a safe manner, which potentially be used a promising therapeutic option.
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Affiliation(s)
- Daniel C. Pan
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Vinu Krishnan
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Alyssa K. Salinas
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Jayoung Kim
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Tao Sun
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Sagi Ravid
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Kevin Peng
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Debra Wu
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Md Nurunnabi
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Jeffery A. Nelson
- Faculty of Arts and Sciences, Division of SciencesHarvard UniversityCambridgeMassachusettsUSA
| | - Zachary Niziolek
- Faculty of Arts and Sciences, Division of SciencesHarvard UniversityCambridgeMassachusettsUSA
| | - Junling Guo
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Samir Mitragotri
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
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14
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Kang YK, Chin K, Chung HC, Kadowaki S, Oh SC, Nakayama N, Lee KW, Hara H, Chung IJ, Tsuda M, Park SH, Hosaka H, Hironaka S, Miyata Y, Ryu MH, Baba H, Hyodo I, Bang YJ, Boku N. S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial. Lancet Oncol 2020; 21:1045-1056. [PMID: 32682457 DOI: 10.1016/s1470-2045(20)30315-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer. METHODS We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593. FINDINGS Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia). INTERPRETATION TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients. FUNDING Taiho Pharmaceutical and Yakult Honsha.
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Affiliation(s)
- Yoon-Koo Kang
- Department of Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
| | - Keisho Chin
- Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hyun Cheol Chung
- Division of Medical Oncology, Institute for Cancer Research, Yonsei University College of Medicine, Yonsei University Health System, Seoul, South Korea
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Centre Hospital, Aichi, Japan
| | - Sang Cheul Oh
- Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, South Korea
| | - Norisuke Nakayama
- Department of Gastroenterology, Kanagawa Cancer Centre, Kanagawa, Japan
| | - Keun-Wook Lee
- Division of Haematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Centre, Saitama, Japan
| | - Ik-Joo Chung
- Department of Haematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, South Korea
| | - Masahiro Tsuda
- Department of Gastroenterological Oncology, Hyogo Cancer Centre, Hyogo, Japan
| | - Se Hoon Park
- Department of Medicine, Division of Haematology-Oncology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hisashi Hosaka
- Department of Gastroenterology, Gunma Prefectural Cancer Centre, Gunma, Japan
| | - Shuichi Hironaka
- Clinical Trial Promotion Department, Chiba Cancer Centre, Chiba, Japan
| | - Yoshinori Miyata
- Department of Medical Oncology, Saku Central Hospital Advanced Care Centre, Nagano, Japan
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hideo Baba
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - Ichinosuke Hyodo
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yung-Jue Bang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Narikazu Boku
- Division of Gastrointestinal Medical Oncology, National Cancer Centre Hospital, Tokyo, Japan.
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Markussen A, Jensen LH, Diness LV, Larsen FO. Treatment of Patients with Advanced Biliary Tract Cancer with Either Oxaliplatin, Gemcitabine, and Capecitabine or Cisplatin and Gemcitabine-A Randomized Phase II Trial. Cancers (Basel) 2020; 12:cancers12071975. [PMID: 32698410 PMCID: PMC7409144 DOI: 10.3390/cancers12071975] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/16/2020] [Accepted: 07/17/2020] [Indexed: 01/06/2023] Open
Abstract
This study is an investigator-initiated randomized phase II trial focusing on the treatment of advanced biliary tract cancer with either oxaliplatin 50 mg/m2 and gemcitabine 1000 mg/m2 on day 1 in a two-week cycle with capecitabine 650 mg/m2 twice-daily continuously or cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and day 8 in a three-week cycle. One-hundred patients were included. Forty-seven patients received oxaliplatin, gemcitabine, and capecitabine with a median progression-free survival (mPFS) of 5.7 months (95% CI 3.0-7.8) and a median overall survival (mOS) of 8.7 months (95% CI 6.5-11.2). Forty-nine patients received cisplatin and gemcitabine with a mPFS of 7.3 months (95% CI 6.0-8.7) and a mOS of 12.0 months (95% CI 8.3-16.7). This trial confirms a mOS of 12 months with cisplatin and gemcitabine, as found in earlier trials. With a superior tumor control rate of 79% vs. 60% (p = 0.045), a difference in the mPFS of 1.6 months (HR = 0.721, p = 0.1), and a difference in the mOS of 3.3 months (HR = 0.731, p = 0.1), cisplatin and gemcitabine should still be considered the standard first-line treatment for advanced biliary tract cancer.
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Affiliation(s)
- Alice Markussen
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark; (L.V.D.); (F.O.L.)
- Correspondence: ; Tel.: +45-38686769
| | | | - Laura Vittrup Diness
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark; (L.V.D.); (F.O.L.)
| | - Finn Ole Larsen
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark; (L.V.D.); (F.O.L.)
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16
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Roosendaal J, Jacobs BAW, Pluim D, Rosing H, de Vries N, van Werkhoven E, Nuijen B, Beijnen JH, Huitema ADR, Schellens JHM, Marchetti S. Phase I pharmacological study of continuous chronomodulated capecitabine treatment. Pharm Res 2020; 37:89. [PMID: 32382808 PMCID: PMC7205843 DOI: 10.1007/s11095-020-02828-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 04/21/2020] [Indexed: 11/30/2022]
Abstract
Purpose Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy). Methods Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8. Results A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment. Conclusion The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1–14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine. Electronic supplementary material The online version of this article (10.1007/s11095-020-02828-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jeroen Roosendaal
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.
| | - Bart A W Jacobs
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.,Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands
| | - Dick Pluim
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands
| | - Hilde Rosing
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands
| | - Niels de Vries
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands
| | - Erik van Werkhoven
- Department of Biometrics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands
| | - Bastiaan Nuijen
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands
| | - Jos H Beijnen
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.,Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508, TB, Utrecht, The Netherlands
| | - Alwin D R Huitema
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.,Department of Clinical Pharmacy, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, The Netherlands
| | - Jan H M Schellens
- Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508, TB, Utrecht, The Netherlands
| | - Serena Marchetti
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands
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17
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Strickler JH, Rushing CN, Niedzwiecki D, McLeod A, Altomare I, Uronis HE, Hsu SD, Zafar SY, Morse MA, Chang DZ, Wells JL, Blackwell KL, Marcom PK, Arrowood C, Bolch E, Haley S, Rangwala FA, Hatch AJ, Nixon AB, Hurwitz HI. A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer. BMC Cancer 2019; 19:1032. [PMID: 31675952 PMCID: PMC6824108 DOI: 10.1186/s12885-019-6234-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 10/02/2019] [Indexed: 12/21/2022] Open
Abstract
Background Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. Methods All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Results A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. Conclusion The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. Trial registration This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.
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Affiliation(s)
- John H Strickler
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA.
| | - Christel N Rushing
- Duke Cancer Institute Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27705, USA
| | - Donna Niedzwiecki
- Duke Cancer Institute Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27705, USA
| | - Abigail McLeod
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - Ivy Altomare
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - Hope E Uronis
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - S David Hsu
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - S Yousuf Zafar
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - Michael A Morse
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - David Z Chang
- Virginia Oncology Associates, Hampton, VA, 23666, USA
| | - James L Wells
- Lexington Oncology Associates, West Columbia, SC, 29169, USA
| | - Kimberly L Blackwell
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - P Kelly Marcom
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - Christy Arrowood
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - Emily Bolch
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - Sherri Haley
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | | | - Ace J Hatch
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
| | - Andrew B Nixon
- Duke University Medical Center, Box 3216, 30 Duke Medicine Circle, Room #0050, Durham, NC, 27705, USA
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18
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Nazari-Vanani R, Karimian K, Azarpira N, Heli H. Capecitabine-loaded nanoniosomes and evaluation of anticancer efficacy. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:420-426. [DOI: 10.1080/21691401.2018.1559179] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- R. Nazari-Vanani
- Nanomedicine and Nanobiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - K. Karimian
- Arasto Pharmaceutical Chemicals Inc, Yousefabad, Tehran, Iran
| | - N. Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - H. Heli
- Nanomedicine and Nanobiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Cockrell C, Axelrod DE. Optimization of Dose Schedules for Chemotherapy of Early Colon Cancer Determined by High-Performance Computer Simulations. Cancer Inform 2019; 18:1176935118822804. [PMID: 30675100 PMCID: PMC6330731 DOI: 10.1177/1176935118822804] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 11/29/2018] [Indexed: 01/08/2023] Open
Abstract
Cancer chemotherapy dose schedules are conventionally applied intermittently, with dose duration of the order of hours, intervals between doses of days or weeks, and cycles repeated for weeks. The large number of possible combinations of values of duration, interval, and lethality has been an impediment to empirically determine the optimal set of treatment conditions. The purpose of this project was to determine the set of parameters for duration, interval, and lethality that would be most effective for treating early colon cancer. An agent-based computer model that simulated cell proliferation kinetics in normal human colon crypts was calibrated with measurements of human biopsy specimens. Mutant cells were simulated as proliferating and forming an adenoma, or dying if treated with cytotoxic chemotherapy. Using a high-performance computer, a total of 28 800 different parameter sets of duration, interval, and lethality were simulated. The effect of each parameter set on the stability of colon crypts, the time to cure a crypt of mutant cells, and the accumulated dose was determined. Of the 28 800 parameter sets, 434 parameter sets were effective in curing the crypts of mutant cells before they could form an adenoma and allowed the crypt normal cell dynamics to recover to pretreatment levels. A group of 14 similar parameter sets produced a minimal time to cure mutant cells. A different group of nine similar parameter sets produced the least accumulated dose. These parameter sets may be considered as candidate dose schedules to guide clinical trials for early colon cancer.
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Affiliation(s)
- Chase Cockrell
- Department of Surgery and Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA
- Department of Surgery, University of Vermont College of Medicine, Burlington, VT, USA
| | - David E Axelrod
- Department of Genetics and Cancer of New Jersey, Rutgers University, Piscataway, NJ, USA
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20
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Standard fluoropyrimidine dosages in chemoradiation therapy result in an increased risk of severe toxicity in DPYD variant allele carriers. Eur J Cancer 2018; 104:210-218. [PMID: 30361102 DOI: 10.1016/j.ejca.2018.07.138] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 07/28/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND Prospective DPYD genotyping prevents severe fluoropyrimidine (FP)-induced toxicity by decreasing dosages in DPYD variant allele carriers. FP dosages in chemoradiation therapy (CRT) are lower than those in other FP-containing regimens. Pharmacogenetic guidelines do not distinguish between regimens, leaving physicians in doubt to apply dose reductions. Our aim was to investigate severe toxicity in DPYD variant allele carriers receiving CRT. METHODS Medical records of 828 patients who received FP-based CRT were reviewed from three centres. Severe (grade ≥III) toxicity in DPYD variant allele carriers receiving upfront FP dose reductions according to pharmacogenetic dosing guidelines and DPYD variant allele carriers not receiving FP dose reductions was compared with DPYD wild-type patients receiving standard dose of FPs in CRT. RESULTS DPYD variant allele carriers treated with standard dosages (N = 34) showed an increased risk of severe gastrointestinal (adjusted OR = 2.58, confidence interval [CI] = 1.02-6.53, P = 0.045) or severe haematological (adjusted OR = 4.19, CI = 1.32-13.25, P = 0.015) toxicity compared with wild-type patients (N = 771). DPYD variant allele carriers who received dose reductions (N = 22) showed a comparable frequency of severe gastrointestinal toxicity compared with wild-type patients, but more (not statistically significant) severe haematological toxicity. Hospitalisations for all DPYD variant allele carriers were comparable, independent of dose adjustments; however, the mean duration of hospitalisation was significantly shorter in the dose reduction group (P = 0.010). CONCLUSIONS Standard FP dosages in CRT resulted in an increased risk of severe toxicity in DPYD variant allele carriers. We advise to apply FP dose reductions according to current guidelines in DPYD variant allele carriers starting CRT.
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21
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Bossi P, Antonuzzo A, Cherny NI, Rosengarten O, Pernot S, Trippa F, Schuler U, Snegovoy A, Jordan K, Ripamonti CI. Diarrhoea in adult cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2018; 29:iv126-iv142. [PMID: 29931177 DOI: 10.1093/annonc/mdy145] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- P Bossi
- Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
| | - A Antonuzzo
- U.O. Oncologia Medica 1, Polo Oncologico Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - N I Cherny
- Oncology Institute, Shaare Zedek Medical Center, Jerusalem, Israel
| | - O Rosengarten
- Oncology Institute, Shaare Zedek Medical Center, Jerusalem, Israel
| | - S Pernot
- Department of Hepato-Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, APHP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - F Trippa
- Radiation Oncology Centre, "S. Maria" Hospital, Terni, Italy
| | - U Schuler
- Department of Internal Medicine I, Palliative Care Centre, University Hospital Carl Gustav Carus, Dresden, Germany
| | - A Snegovoy
- N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
| | - K Jordan
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - C I Ripamonti
- Oncology-Supportive Care in Cancer Unit, Department Onco-Haematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Silva JMD, Lima BDS, Araújo TLD, Lima FET, Cunha GHD. Cardiovascular adverse events associated with oral antineoplastic therapy. Rev Bras Enferm 2018; 71:2561-2569. [PMID: 30304190 DOI: 10.1590/0034-7167-2017-0450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 10/18/2017] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To identify in the literature the cardiovascular adverse events resulting from oral antineoplastic therapy. METHOD Integrative review of the literature through the SCOPUS, Scientific Electronic Library Online (SciELO), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medical Literature Analysis and Retrieval System Online (MEDLINE) databases. The antineoplastic, cardiotoxicity, cardiovascular system and adverse reaction descriptors were used in Portuguese, English and Spanish. We selected 23 articles published between 1985 and 2015. RESULTS Twenty studies were related to cardiac events and eleven to peripheral vascular events. The most frequent adverse cardiac events were reduced left ventricular ejection fraction, myocardial infarction, changes in the electrocardiogram, heart failure and angina, whereas peripheral vascular events were hypertension and thromboembolism. CONCLUSION Oral antineoplastic therapy is associated with different adverse events, including cardiac and peripheral vascular events.
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Affiliation(s)
- Jacqueline Mota da Silva
- Universidade Federal do Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Nursing. Fortaleza, Ceará, Brazil
| | - Beatriz da Silva Lima
- Universidade Federal do Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Nursing. Fortaleza, Ceará, Brazil
| | - Thelma Leite de Araújo
- Universidade Federal do Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Nursing. Fortaleza, Ceará, Brazil
| | | | - Gilmara Holanda da Cunha
- Universidade Federal do Ceará, Faculty of Pharmacy, Dentistry and Nursing, Department of Nursing. Fortaleza, Ceará, Brazil
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23
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Phase Ib trial combining capecitabine, erlotinib and bevacizumab in pancreatic adenocarcinoma - REBECA trial. Invest New Drugs 2018; 37:127-138. [PMID: 29998365 DOI: 10.1007/s10637-018-0639-0] [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: 03/11/2018] [Accepted: 07/06/2018] [Indexed: 11/27/2022]
Abstract
Background Purpose of this phase Ib trial was to establish the maximum tolerable dose (MTD) of capecitabine and to escalate the dosages of erlotinib and bevacizumab to determine the recommended phase II dose (RP2D) in patients with advanced/metastatic pancreatic adenocarcinoma not pretreated for metastatic disease. Methods Starting doses were capecitabine 500 mg/m2 bid orally continuously, erlotinib 100 mg orally daily, and bevacizumab 5 mg/kg intravenously q 2 weeks. Dose escalation was performed according to a 3 + 3 design for capecitabine until MTD, for erlotinib and bevacizumab until the maximum doses registered by applying a substance-related, toxicity-based scheme accompanied by pharmacokinetic analysis. Circulating tumor cells (CTCs) were determined pretherapeutically by immunohistochemical identification after enrichment with immunomagnetic separation. Results Thirty patients were evaluable at six dose levels. 900 mg/m2 bid were determined as MTD for capecitabine based on dose-limiting toxicities: cutaneous in two patients and vascular in another. The most severe (Grade (G)3/4) drug-related treatment-emergent adverse events (toxicities) belonged to the categories gastrointestinal, vascular, cutaneous, cardiovascular, metabolic/nutritional or hematological. G3 toxicities occurred in 14 (47%), G3 + G4 in a single (3%) patient. 2 out of 28 patients (7%) exerted partial response, 17 (61%) stable disease. Pharmacokinetic evaluation revealed lack of drug-drug interaction between capecitabine and erlotinib and their metabolites. Presence of CTCs was associated with shorter progression-free survival (p = 0.009). Conclusions The study met the primary objective. RP2D was capecitabine 800 mg/m2 bid continuously, erlotinib 150 mg daily, and bevacizumab 10 mg/kg q 2 weeks. The regimen could be applied safely, but demonstrated limited efficacy.
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24
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Bertolini A, Flumanò M, Fusco O, Muffatti A, Scarinci A, Pontiggia G, Scopelliti M. Acute Cardiotoxicity during Capecitabine Treatment: A Case Report. TUMORI JOURNAL 2018; 87:200-6. [PMID: 11504378 DOI: 10.1177/030089160108700317] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Capecitabine (Xeloda®, Roche, Monza), a fluoropyrimidine carbamate, is an orally administered drug that delivers fluorouracil (5-FU) selectively to the tumor. The drug has demonstrated activity in metastatic breast cancer, pancreatic cancer and colorectal cancer. In this case report the authors describe an unusually and reversible cardiac side effect which occurs to 39-year-old patient treated with capecitabine 2000 mg/m2/day for advanced gastric cancer. It is important to note that the safety data from clinical trials indicate that capecitabine has a toxicity profile typical of infused fluoropyrimidines. However, none of the studies described cardiac side effects.
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Affiliation(s)
- A Bertolini
- Division of Medical Oncology, Ospedale di Sondrio, Italy.
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25
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Cassata A, Procoplo G, Alù M, Ferrari L, Ferrario E, Beretta E, Longarini R, Busto G, De Candis D, Bajetta E. Capecitabine: Indications and Future Perspectives in the Treatment of Metastatic Colorectal and Breast Cancer. TUMORI JOURNAL 2018; 87:364-71. [PMID: 11989587 DOI: 10.1177/030089160108700602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Fluoropyrimidines remain the most important drugs in the treatment of breast and colorectal carcinoma, but response rates and survival time have been disappointing. Optimal administration is by continuous intravenous infusion, which makes it cumbersome to use and compromises patient independence. Recently, a number of new agents, including fluorouracil prodrugs and selective dihydropyrimidine dehydrogenase inhibitors, have been studied, with promising results. Capecitabine is the first in a new class of fluoropyrimidines. It is an oral, tumor-activated anticancer drug whose activity mimics that of continuously infused 5-fluorouracil. Capecitabine circumvents dihydropyrimidine dehydrogenase catabolism and appears to be at least as active against metastatic colorectal and breast cancer as conventionally administered intravenous 5-fluorouracil, with significantly less toxicity, an improved quality of life, and lesser cost. Capecitabine may ultimately provide enhanced antitumor activity to fluorouracil-containing regimes for advanced colorectal and breast cancer.
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Affiliation(s)
- A Cassata
- Medical Oncology Unit B, National Cancer Institute, Milan, Italy
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26
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Ardito F, Pellegrino MR, Perrone D, Troiano G, Cocco A, Lo Muzio L. In vitro study on anti-cancer properties of genistein in tongue cancer. Onco Targets Ther 2017; 10:5405-5415. [PMID: 29180873 PMCID: PMC5692202 DOI: 10.2147/ott.s133632] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Purpose Tongue cancer is an extremely aggressive disease and is characterized by a poor prognosis. It is a complex disease to treat and current therapies have produced mediocre results with many side effects. Some facts suggest that natural essences can support traditional cancer therapy by carrying out a synergistic function with chemotherapy. Therefore, we evaluated the antitumor effects of genistein on tongue carcinoma cells. Methods Genistein 20, 50 and 100 µM were used for 24, 48 and 72 hours on 3 tongue carcinoma cell lines. xCELLigence system was used to evaluate the effects on cell adhesion, proliferation and to calculate IC50 values. Both MTT assay and Trypan blue assay were used to evaluate alterations in cell viability, scratch assay for cell migration and Western blot analysis for expression of some proteins. Results Cell adhesion was inhibited especially between 20 and 50 µM of genistein treatment. Proliferation was reduced by 50% for treatments with 20 µM at 24 hours, with 20 or 50 µM at 48 and 50 µM at 72 hours (P<0.0001). Viability tests confirmed a proportional reduction in concentration of genistein and duration of treatments. Even cell migration was reduced significantly (P<0.001). Genistein down-regulates vitronectin, OCT4 and survivin. Conclusion This in vitro study clarifies the anti-tumor effect of genistein on tongue carcinoma. In vivo studies are needed to confirm these data and develop a suitable delivery system that is capable of acting directly on tumor.
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Affiliation(s)
- Fatima Ardito
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
| | - Mario R Pellegrino
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
| | - Donatella Perrone
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
| | - Giuseppe Troiano
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
| | - Armando Cocco
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
| | - Lorenzo Lo Muzio
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
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27
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Thorat SG, Chikhale RV, Tajne MR. A rapid and simple HPTLC assay for therapeutic drug monitoring of capecitabine in colorectal cancer patients. Biomed Chromatogr 2017; 32. [DOI: 10.1002/bmc.4100] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 09/13/2017] [Accepted: 09/14/2017] [Indexed: 11/10/2022]
Affiliation(s)
- Sonali G. Thorat
- Department of Pharmaceutical Sciences; Rashtrasant Tukadoji Maharaj Nagpur University; Nagpur India
| | - Rupesh V. Chikhale
- Division of Pharmacy and Optometry; University of Manchester; Manchester UK
| | - Madhukar R. Tajne
- Department of Pharmaceutical Sciences; Rashtrasant Tukadoji Maharaj Nagpur University; Nagpur India
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28
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Li J, Xu R, Xu J, Denda T, Ikejiri K, Shen L, Toh Y, Shimada K, Kato T, Sakai K, Yamamoto M, Mishima H, Wang J, Baba H. Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer: Regimen of 1 week on, 1 week off. Cancer Sci 2017; 108:2045-2051. [PMID: 28763145 PMCID: PMC5623741 DOI: 10.1111/cas.13335] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 07/04/2017] [Accepted: 07/15/2017] [Indexed: 12/03/2022] Open
Abstract
A phase II study of S‐1 plus leucovorin (LV) given in a 4‐week schedule (2 weeks’ administration followed by 2 weeks’ rest) for patients with untreated metastatic colorectal cancer (mCRC) showed that the combination was effective, but grade 3 toxicities (diarrhea, stomatitis and anorexia) occurred at a relatively high rate. In this phase II study, we evaluated the efficacy and safety of a 2‐week schedule of S‐1 plus LV. Patients with mCRC received oral S‐1 (40–60 mg) and LV (25 mg) twice daily for 1 week, followed by 1 week's rest. Treatment was repeated until disease progression or unacceptable toxicity. The primary endpoint was response rate. The pharmacokinetics of S‐1 and LV in Chinese patients were evaluated on day 1 of the first cycle. Seventy‐three patients were enrolled in Japan and China. Of 71 eligible patients, the response rate was 53.5%, and the disease control rate was 83.1%. Median progression‐free survival and median overall survival were 6.5 and 24.3 months, respectively. The incidences of grade 3 toxicities were diarrhea 8.3%, stomatitis 8.3%, anorexia 2.8% and neutropenia 9.7%. There were no treatment‐related deaths. The pharmacokinetics profiles of S‐1 plus LV in Chinese patients were similar to those in Japanese patients. This 2‐week schedule of S‐1 plus LV showed good efficacy and better tolerability than the 4‐week schedule. This therapy will be the base regimen for mCRC to be added by other cytotoxic or molecular‐targeted drugs. The optimized treatment schedule for S‐1 plus LV was 1 week on and 1 week off.
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Affiliation(s)
- Jin Li
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ruihua Xu
- Division of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China
| | - Jianming Xu
- No. 4 Division of Oncology, People's Liberation Army No. 307 Hospital, Beijing, China
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba City, Japan
| | - Koji Ikejiri
- Department of Surgery, Gastroenterology Center, National Hospital Organization Kyushu Medical Center, Fukuoka City, Japan
| | - Lin Shen
- Digestive System Medicine Department, Beijing Cancer Hospital, Beijing, China
| | - Yasushi Toh
- Department of Gastroenterological Surgery, National Hospital Organization, National Kyushu Cancer Center, Fukuoka City, Japan
| | - Ken Shimada
- Department of Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama City, Japan
| | - Takeshi Kato
- Department of Surgery, Minoh City Hospital, Minoh City, Japan
| | - Kenji Sakai
- Department of Medical Oncology, Saiseikai Kumamoto Hospital, Kumamoto City, Japan
| | - Manabu Yamamoto
- Department of Surgery, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima City, Japan
| | - Hideyuki Mishima
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka City, Japan
| | - Jinwan Wang
- Division of Oncology, Chinese Institute & Hospital Chinese Academy of Medical Sciences, Beijing, China
| | - Hideo Baba
- Gastroenterological Surgery, Kumamoto University Hospital, Kumamoto City, Japan
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Miura K, Shima H, Takebe N, Rhie J, Satoh K, Kakugawa Y, Satoh M, Kinouchi M, Yamamoto K, Hasegawa Y, Kawai M, Kanazawa K, Fujiya T, Unno M, Katakura R. Drug delivery of oral anti-cancer fluoropyrimidine agents. Expert Opin Drug Deliv 2017; 14:1355-1366. [PMID: 28379040 DOI: 10.1080/17425247.2017.1316260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.
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Affiliation(s)
- Koh Miura
- a Department of Surgery , Miyagi Cancer Center , Natori , Japan
| | - Hiroshi Shima
- b Division of Cancer Chemotherapy , Miyagi Cancer Center Research Institute , Natori , Japan
| | - Naoko Takebe
- c Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Investigational Drug Branch , National Institutes of Health, National Cancer Institute , Bethesda , MD , USA
| | - Julie Rhie
- d Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Regulatory Affairs Branch , National Institutes of Health, National Cancer Institute , Bethesda , MD , USA
| | - Kennichi Satoh
- e Miyagi Cancer Center Research Institute , Division of Cancer Stem Cell , Natori , Japan
| | - Yoichiro Kakugawa
- f Department of Breast Oncology , Miyagi Cancer Center , Natori , Japan
| | - Masayuki Satoh
- a Department of Surgery , Miyagi Cancer Center , Natori , Japan
| | - Makoto Kinouchi
- a Department of Surgery , Miyagi Cancer Center , Natori , Japan
| | | | | | - Masaaki Kawai
- f Department of Breast Oncology , Miyagi Cancer Center , Natori , Japan
| | | | - Tsuneaki Fujiya
- a Department of Surgery , Miyagi Cancer Center , Natori , Japan
| | - Michiaki Unno
- g Department of Surgery , Tohoku University Graduate School of Medicine , Sendai , Japan
| | - Ryuichi Katakura
- h Department of Neurosurgery , Miyagi Cancer Center , Natori , Japan
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Axelrod DE, Vedula S, Obaniyi J. Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study. Cancer Chemother Pharmacol 2017; 79:889-898. [PMID: 28343282 DOI: 10.1007/s00280-017-3272-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 03/01/2017] [Indexed: 12/09/2022]
Abstract
PURPOSE The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function. METHODS A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function. RESULTS Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug. CONCLUSIONS An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.
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Affiliation(s)
- David E Axelrod
- Department of Genetics and Cancer Institute of New Jersey, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854-8082, USA.
| | - Sudeepti Vedula
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ, 08854, USA
- Department of Molecular Biology and Biochemistry, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854-8082, USA
| | - James Obaniyi
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ, 08854, USA
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31
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Woo IS, Jung YH. Metronomic chemotherapy in metastatic colorectal cancer. Cancer Lett 2017; 400:319-324. [PMID: 28274890 DOI: 10.1016/j.canlet.2017.02.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/26/2017] [Accepted: 02/27/2017] [Indexed: 02/06/2023]
Abstract
Overall survival and quality of life of patients with metastatic colorectal cancer (mCRC) have improved due to the development of standard systemic treatment. However, many patients are still suffering from the eventual progression of cancer, treatment-related toxicities, and the economic burden of new drugs. Salvage or maintenance therapy, which consistently controls or stabilizes tumor progression without debilitating quality of life, is required. Recently, metronomic capecitabine maintenance therapy after disease control using conventional chemotherapy with maximal tolerated doses has demonstrated beneficial results in a phase III trial. Metronomic chemotherapy has been known to control tumors through antiangiogenesis and immunomodulation as well as a direct effect on tumor-initiating cells. It has the characteristics of being minimally toxic, inexpensive, and durable for maintaining disease stabilization. Therefore, patients with mCRC, who tend to be elderly and frail and have been previously treated, might be suitable for metronomic therapeutic strategies. Furthermore, antiangiogenic therapy has been an important component in treating mCRC, but the schedules and doses of metronomic chemotherapy have not yet been established. Here we review translational and clinical research on metronomic chemotherapy in colorectal cancer (CRC).
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Affiliation(s)
- In Sook Woo
- Division of Medical Oncology, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 10, 63-ro, Yeongdeungpo-gu, Seoul, 07345, Republic of Korea.
| | - Yun Hwa Jung
- Division of Medical Oncology, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 10, 63-ro, Yeongdeungpo-gu, Seoul, 07345, Republic of Korea
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Phase I clinical and pharmacokinetic study of S-1 plus oral leucovorin in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 2016; 79:107-116. [DOI: 10.1007/s00280-016-3212-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 11/29/2016] [Indexed: 10/20/2022]
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Effect of Neoadjuvant Chemoradiotherapy with Capecitabine versus Fluorouracil for Locally Advanced Rectal Cancer: A Meta-Analysis. Gastroenterol Res Pract 2016; 2016:1798285. [PMID: 27891147 PMCID: PMC5116508 DOI: 10.1155/2016/1798285] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 06/30/2016] [Indexed: 11/17/2022] Open
Abstract
A meta-analysis was carried out to compare the efficacy and safety of capecitabine plus radiation with 5-fluorouracil (5-FU) plus radiotherapy (RT) as neoadjuvant treatment in locally advanced rectal cancer (LARC). We searched the Cochrane database, Ovid, Medline, Embase, ISI databases, and Chinese Biomedical Literature Database between January 1998 and October 2014. Trials of capecitabine compared with 5-FU plus RT as neoadjuvant treatment for LARC were considered for inclusion. RevMan software was used to analyze these data. Nine trials were included in this meta-analysis, which covered a total of 3141 patients. The meta-analysis showed that capecitabine group had statistically significant better pCR rates (OR, 1.34; 95% CI, 1.10-1.64; P = 0.003), T downstaging rates (OR, 1.58; 95% CI, 1.22-2.06; P = 0.0007), N downstaging rates (OR, 2.06; 95% CI, 1.34-3.16; P = 0.001), less distant metastasis (OR, 0.63; 95% CI, 0.44-0.88; P = 0.007), and lowered leucocytes (OR, 0.25; 95% CI, 0.11-0.54; P = 0.0005), but with higher incidence of hand-foot syndrome (HFS) (OR, 4.43; 95% CI, 1.59-12.33; P = 0.004). Capecitabine was more efficient than 5-FU in terms of tumor response in neoadjuvant treatment for patients with LARC and favourably low toxicity with the exception of HFS.
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Li X, Shi L, Wu J, Ji M, Zhao J, Qiang W, Ding W, Jiang J, Lu Q, Wu C. First-line treatment with hepatic arterial infusion plus capecitabine vs capecitabine alone for elderly patients with unresectable colorectal liver metastases. Cancer Biol Ther 2016; 17:14-9. [PMID: 26619222 DOI: 10.1080/15384047.2015.1108487] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
This study aimed to compare the efficacy and safety of HAI fluoropyrimidine (FUDR)/capecitabine or single capecitabine as first-line treatment for elderly patients with unresectable colorectal liver metastases (CLMs). Fifty-one elderly patients with liver-only CLMs were eligible for enrollment. Patients were divided into HAI FUDR /capecitabine group and single capecitabine group randomly. The primary endpoint was median survival time (MST), defined as the time from the date of catheter implantation to the date of death or the date of the last follow-up. The secondary endpoint was objective antitumor response and adverse events. The HAI pump was implanted before chemotherapy. All patients received a 3-week cycle of oral capecitabin. In Group A, the RR and DCR were both 95.8%. In Group B, the RR and DCR were 48.1% and 81.5%, respectively. There was significant difference between the RRs of the 2 groups (P < 0.001). But there was no significant difference between the DCRs of the 2 groups (P = 0.053). There was a statistical difference between the MSTs of the 2 groups (18.5 vs.13 months, P = 0.0312). HAI FUDR combined with oral capecitabine as the first-line treatment for elderly patients with CLMs has promising efficacy and safety.
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Affiliation(s)
- Xiaodong Li
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China.,b Department of Biological Treatment , The Third Affiliated Hospital of Soochow University Changzhou , China.,c Jiangsu Engineering Research Center for Tumor Immunotherapy Changzhou , China
| | - Liangrong Shi
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China.,c Jiangsu Engineering Research Center for Tumor Immunotherapy Changzhou , China
| | - Jun Wu
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Mei Ji
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Jiemin Zhao
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Weiguang Qiang
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Wenge Ding
- d Department of Orthopedics , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Jingting Jiang
- b Department of Biological Treatment , The Third Affiliated Hospital of Soochow University Changzhou , China.,c Jiangsu Engineering Research Center for Tumor Immunotherapy Changzhou , China
| | - Qicheng Lu
- e Department of Gastrointestinal Surgery , The Third Affiliated Hospital of Soochow University Changzhou , China
| | - Changping Wu
- a Department of Oncology , The Third Affiliated Hospital of Soochow University Changzhou , China.,b Department of Biological Treatment , The Third Affiliated Hospital of Soochow University Changzhou , China.,c Jiangsu Engineering Research Center for Tumor Immunotherapy Changzhou , China
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35
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Syn N, Lee SC, Goh BC, Yong WP. Capecitabine pharmacogenetics: historical milestones and progress toward clinical implementation. Pharmacogenomics 2016; 17:1607-1610. [DOI: 10.2217/pgs-2016-0133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Nicholas Syn
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600
| | - Soo-Chin Lee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
| | - Boon-Cher Goh
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600
| | - Wei-Peng Yong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
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36
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Summerhayes M. Capecitabine: a novel, orally administered, tumour-activated treatment for breast cancer. J Oncol Pharm Pract 2016. [DOI: 10.1191/1078155202jp086oa] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Objective. To provide a comprehensive review of the preclinical and clinical pharmacology and toxicology of the fluoropyrimidine, capecitabine, with particular reference to its use in metastatic breast cancer. Data Sources. A MEDLINE search was conducted using the term ‘capecitabine’ for the period 1995 -2001. The reference lists from retrieved articles were reviewed and other relevant papers identified. The abstract books from the annual meetings of the American Society of Clinical and Oncology and the European Society of Medical Oncology were also reviewed. Data Extraction. The aim of the review was to be comprehensive and descriptive. All studies containing information deemed to be of interest were reviewed by the author; none was excluded on grounds of quality. Data Summary. Capecitabine is a prodrug of the widely used cytotoxic agent 5-fluorouracil (5-FU). Unlike 5-FU, it is extensively and reliably absorbed after oral administration and does not require folinate (FA) potentiation. The activation of capecitabine is a three-step enzymatic process. The final activating enzyme - thymidine phosphorylase - is found in unusually high concentrations in many solid tumours including breast cancers, resulting in preferential delivery of 5-FU to tumour tissues, and suggesting a greater potential for selective cytotoxicity than is seen with 5-FU. Capecitabine has been examined both alone and in combination with a variety of cytotoxic drugs in the treatment of metastatic breast cancer. To date, clinical evidence supports the use of capecitabine monotherapy in patients relapsing after prior treatment with anthracyclines and taxanes and in combination with docetaxel in patients failing anthracycline treatment. Data from phase II studies indicate that in the first of these situations, capecitabine elicits a response in about one-fifth of patients and that responses are associated with symptomatic relief and extended survival. In the latter situation, a phase III study has shown that the combination of docetaxel and capecitabine elicits superior response rates, remission durations, and overall survival compared with the taxane alone and with no clinically important increase in toxicity. Used alone or in combination, the most notable adverse effect associated with capecitabine is palmar-plantar erythrodysasthesia (hand -foot syndrome), a characteristic complex of reddening, dryness, and soreness of the palms of the hands and soles of the feet, which is rarely disabling and readily managed by treatment interruption and dose reduction.
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Summerhayes M. Capecitabine: a novel, orally administered, tumour-activated treatment for colorectal cancer. J Oncol Pharm Pract 2016. [DOI: 10.1191/1078155201jp085oa] [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]
Abstract
Objective. To provide a comprehensive review of the preclinical and clinical pharmacology and toxicology of the fluoropyrimidine, capecitabine, with particular reference to its use in its new indication, advanced colorectal cancer. Data sources. A MEDLINE search was conducted using the term ‘‘capecitabine’’ for the period 1995 -2001. The reference lists from retrieved articles were reviewed and other relevant papers identified. The abstract books from the annual meetings of the American Society of Clinical and Oncology and the European Society of Medical Oncology were also reviewed. Data extraction. The aim of the review was to be comprehensive and descriptive. All studies containing information deemed to be of interest were reviewed by the author, none were excluded on grounds of quality. Data synthesis. Capecitabine is a prodrug of the widely used cytotoxic agent 5-fluorouracil (5-FU). Unlike 5-FU it is extensively and reliably absorbed after oral administration and does not require folinate (FA) potentiation. Activation of capecitabine is a three-step enzymatic process. The final activating enzyme, thymidine phosphorylase, is found in unusually high concentrations in many solid tumours, resulting in preferential delivery of 5-FU to tumour tissues, including that of colorectal cancers, suggesting therapeutic potential in this malignancy. Large, randomized trials have demonstrated that capecitabine fulfils this potential—compared with the widely used ‘‘Mayo’’ regimen of intravenous 5-FU and folinic acid, oral capecitabine (1250 mg/m2 twice daily) produced a superior response rate and a similar time to disease progression and duration of survival. It was also better tolerated than 5-FU/FA—of seven common fluoropyrimidine-induced toxicities, four were significantly less common with capecitabine. Capecitabine also produced significantly less grade 4 toxicity or toxicity requiring hospitalization, though the hand -foot syndrome that characterizes prolonged, continuous exposure to 5-FU was more common after capecitabine.
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Affiliation(s)
- Maxwell Summerhayes
- The Pharmacy Department, Guy’s Hospital, St. Thomas’ Street, London SE1 9RT, UK
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Abstract
Objective. To provide a comprehensive review of the chemotherapy induced dermatological toxi-city, palmar-plantar erythrodysesthesia (PPE), including clinical presentation, drugs implication in causing the reaction, and approaches for management. Data sources. A search of MEDLINE (1966-2002), IDIS (1985- 2002) and CANCERLIT (1993-2002) databases was conducted using the terms (and variations of the terms) palmar-plantar erythrodysesthesia, hand-foot syndrome, and acral erythema. Bibliographies from selected articles were also reviewed for appropriate references. Data extraction. The retrieved literature was reviewed to include all articles pertaining to the incidence, clinical presentation, mechanism, pathology, diagnosis, treatment and prevention of PPE. Data synthesis. PPE is a distinctive, localized cutaneous reaction to certain antineoplastic agents. A number of drugs have been implicated, including most commonly cytarabine, fluorouracil, doxorubicin, and capecitabine. There appears to be an association with administration schedules that lead to elevated peak plasma concentrations, such as in high-dose therapy, or after prolonged periods of constant exposure, as with continuous infusions, regular oral dosing, or liposomal formulations. The extent and severity of the reaction, time of onset, and duration are variable. Symptoms can occur to both hands and feet, and include dysesthesia, paresthesia, erythema, swelling, pain, blistering, ulceration, and desquamination. Cessation of the offending agent appears to be the most important step in the management of PPE. Dose modification may be necessary for subsequent cycles. As the course of PPE is self-limiting, treatment is commonly supportive and based on the type and severity of symptoms encountered. This can include analgesia, emollient or soothing creams, wound care, and cold compresses. Administration of corticosteroids has produced mixed results. Pyridoxine shows promise as both a treatment and preventative strategy, although confirmation in prospective clinical trials is needed. Advice should be provided to patients to ensure prompt recognition of toxicity and plans for prevention and amelioration of symptoms provided.
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Affiliation(s)
- Peter Gilbar
- Department of Pharmacy, Toowoomba Health Services, PMB 2, Toowoomba, Australia
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Kwakman J, Punt C. Oral drugs in the treatment of metastatic colorectal cancer. Expert Opin Pharmacother 2016; 17:1351-61. [DOI: 10.1080/14656566.2016.1186649] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Abstract
INTRODUCTION With an increasing incidence, over half a million cases of head and neck cancer (HNC) are diagnosed annually worldwide. Various chemotherapeutic agents are utilized to achieve adequate locoregional control. Cisplatin, fluorouracil (FU), and taxanes are often used to treat HNC but these regimens have shown high toxicity and poor patient compliance. Capecitabine is an orally administered prodrug that is preferentially converted to FU in tumor cells in comparison to normal cells. AREA COVERED In this review, the authors evaluate the role of capecitabine in radical and palliative settings either alone or in combination with other chemotherapeutic drugs in the management of HNC. In addition, metabolic conversion, pharmacokinetics, pharmacodynamics, and toxicity profile of capecitabine are discussed. EXPERT OPINION Various phase II trials conducted on capecitabine in the management of recurrent HNC have shown comparable results and tolerable toxic effects especially in pre-treated fragile patients. Capecitabine, used in induction or concurrent settings in the radical management of locoregionally advanced HNC, have also shown promising results. Randomized trials are needed to validate the role of capecitabine in the management of HNC.
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Affiliation(s)
- Hassan Iqbal
- a Department of Otolaryngology - Head and Neck Surgery , The Ohio State University Wexner Medical Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center , Columbus , OH , USA
| | - Quintin Pan
- a Department of Otolaryngology - Head and Neck Surgery , The Ohio State University Wexner Medical Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center , Columbus , OH , USA
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Kobashi N, Matsumoto H, Zhao S, Meike S, Okumura Y, Abe T, Akizawa H, Ohkura K, Nishijima KI, Tamaki N, Kuge Y. The Thymidine Phosphorylase Imaging Agent 123I-IIMU Predicts the Efficacy of Capecitabine. J Nucl Med 2016; 57:1276-81. [DOI: 10.2967/jnumed.115.165811] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 03/11/2016] [Indexed: 12/27/2022] Open
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Ueno M, Okusaka T, Omuro Y, Isayama H, Fukutomi A, Ikeda M, Mizuno N, Fukuzawa K, Furukawa M, Iguchi H, Sugimori K, Furuse J, Shimada K, Ioka T, Nakamori S, Baba H, Komatsu Y, Takeuchi M, Hyodo I, Boku N. A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer. Ann Oncol 2015; 27:502-8. [PMID: 26681680 PMCID: PMC4769993 DOI: 10.1093/annonc/mdv603] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 12/01/2015] [Indexed: 12/27/2022] Open
Abstract
This is the first phase II trial in which adding oral leucovorin (LV) to S-1 (SL) significantly prolonged progression-free survival (PFS) when compared with S-1 monotherapy (S) in patients with gemcitabine-refractory advanced pancreatic cancer (PC). The significantly better PFS and disease control rate with SL than with S suggest that the antitumor activity of S-1 is enhanced by LV in advanced PC. Background We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC). Patients and methods Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS). Results Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37–0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54–1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47–1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group. Conclusion The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting. Clinical trials number Japan Pharmaceutical Information Center: JapicCTI-111554.
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Affiliation(s)
- M Ueno
- Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama
| | - T Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo
| | - Y Omuro
- Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo
| | - H Isayama
- Department of Gastroenterology, The University of Tokyo, Graduate School of Medicine, Tokyo
| | - A Fukutomi
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka
| | - M Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa
| | - N Mizuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya
| | - K Fukuzawa
- Department of Surgery, Oita Red Cross Hospital, Oita
| | - M Furukawa
- Department of Gastroenterology, National Kyushu Cancer Center, Fukuoka
| | - H Iguchi
- Department of Gastroenterology, National Hospital Organization Shikoku Cancer Center, Matsuyama
| | - K Sugimori
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama
| | - J Furuse
- Department of Medical Oncology, Kyorin University School of Medicine, Tokyo
| | - K Shimada
- Department of Medical Oncology, Saitama Medical University International Medical Center, Saitama
| | - T Ioka
- Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka
| | - S Nakamori
- Hepato-biliary-pancreatic Surgery, National Hospital Organization Osaka National Hospital, Osaka
| | - H Baba
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto
| | - Y Komatsu
- Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo
| | - M Takeuchi
- Department of Clinical Medicine (Biostatistics and Pharmaceutical Medicine), Kitasato University School of Pharmacy, Tokyo
| | - I Hyodo
- Division of Gastroenterology, University of Tsukuba, Tsukuba
| | - N Boku
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan
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Hironaka S, Sugimoto N, Yamaguchi K, Moriwaki T, Komatsu Y, Nishina T, Tsuji A, Nakajima TE, Gotoh M, Machida N, Bando H, Esaki T, Emi Y, Sekikawa T, Matsumoto S, Takeuchi M, Boku N, Baba H, Hyodo I. S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial. Lancet Oncol 2015; 17:99-108. [PMID: 26640036 DOI: 10.1016/s1470-2045(15)00410-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 10/07/2015] [Accepted: 10/09/2015] [Indexed: 01/08/2023]
Abstract
BACKGROUND Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer. METHODS In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2) on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m(2) on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635. FINDINGS Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3-57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7-79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4-60·8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]). INTERPRETATION S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway. FUNDING Taiho Pharmaceutical.
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Affiliation(s)
| | - Naotoshi Sugimoto
- Osaka Medical Centre for Cancer and Cardiovascular Diseases, Osaka, Japan
| | | | | | | | - Tomohiro Nishina
- National Hospital Organization Shikoku Cancer Centre, Matsuyama, Japan
| | - Akihito Tsuji
- Kobe City Medical Centre General Hospital, Kobe, Japan
| | | | | | | | - Hideaki Bando
- National Cancer Centre Hospital East, Kashiwa, Japan
| | - Taito Esaki
- National Hospital Organization Kyushu Cancer Centre, Fukuoka, Japan
| | - Yasunori Emi
- Saiseikai Fukuoka General Hospital, Fukuoka, Japan
| | | | | | | | - Narikazu Boku
- St Marianna University School of Medicine, Kawasaki, Japan
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Hagman H, Frödin JE, Berglund Å, Sundberg J, Vestermark LW, Albertsson M, Fernebro E, Johnsson A. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol 2015; 27:140-7. [PMID: 26483047 DOI: 10.1093/annonc/mdv490] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 10/06/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap). PATIENTS AND METHODS Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed. RESULTS We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C). CONCLUSIONS Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results. CLINICALTRIALSGOV NCT01229813.
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Affiliation(s)
- H Hagman
- Department of Oncology, County Hospital Ryhov, Jönköping
| | - J-E Frödin
- Department of Oncology, Karolinska University Hospital, Stockholm
| | - Å Berglund
- Department of Oncology, Uppsala University Hospital, Uppsala
| | - J Sundberg
- Department of Oncology, Skåne University Hospital, Lund/Malmö, Sweden
| | - L W Vestermark
- Department of Oncology, Odense University Hospital, Odense, Denmark
| | - M Albertsson
- Department of Oncology, Linköping University Hospital, Linköping
| | - E Fernebro
- Department of Oncology, Växjö Hospital, Växjö, Sweden
| | - A Johnsson
- Department of Oncology, Skåne University Hospital, Lund/Malmö, Sweden
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Han L, Sun YJ, Pan YF, Ding H, Chen X, Zhang X. Cantharidin combined with chemotherapy for Chinese patients with metastatic colorectal cancer. Asian Pac J Cancer Prev 2015; 15:10977-9. [PMID: 25605212 DOI: 10.7314/apjcp.2014.15.24.10977] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND This systematic analysis was conducted to evaluate the efficacy and safety of cantharidin combined with chemotherapy in treating Chinese patients with metastatic colorectal cancer. METHODS Clinical studies evaluating the efficacy and safety of cantharidin combined with chemotherapy on response and safety for Chinese patients with colorectal cancer were identified using a predefined search strategy. Pooled response rate (RR) of treatment were calculated. RESULTS When cantharidin combined with chemotherapy, 4 clinical studies which included 155 patients with advanced colorectal cancer were considered eligible for inclusion. The systematic analysis suggested that, in all patients, pooled RR was 46.5% (72/155) in cantharidin combined regimens. Major adverse effects were neutropenia, leukopenia, fatigue, and anemia with cantharidin combined treatment; no treatment related deaths occurred. CONCLUSION This systematic analysis suggests that cantharidin combined regimens are associated with high response rate and accepted toxicity in treating Chinese patients with metastatic colorectal cancer suggesting that randomized clinical trials are now warranted.
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Affiliation(s)
- Li Han
- Department of Traditional Chinese Medicine, Huadong Hospital of Fudan University, Shanghai, China E-mail :
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Murad AM, Murad LS. First-Line Therapy in Metastatic Colorectal Cancer Patients Not Candidates for Curative Surgery. CURRENT COLORECTAL CANCER REPORTS 2015. [DOI: 10.1007/s11888-015-0259-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Choi DR, Yoon SN, Kim HS, Kim JH, Kim KY, Kim BC, Choi YK, Kim JB, Han B, Song HH, Zang DY. A phase II study of capecitabine and oral leucovorin as a third-line chemotherapy in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 2015; 75:639-43. [PMID: 25630415 DOI: 10.1007/s00280-015-2688-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 01/18/2015] [Indexed: 12/27/2022]
Abstract
PURPOSE This study was conducted to evaluate the efficacy and safety of the combination of capecitabine and oral leucovorin (LV) as a third-line chemotherapy for patients with metastatic colorectal cancer (CRC) showing resistance to irinotecan- and oxaliplatin-containing regimens. METHOD Patients who showed disease progression while receiving or within 6 months of discontinuing irinotecan- and oxaliplatin-containing regimens received capecitabine 825 mg/m(2) in combination with oral LV at a fixed dose of 30 mg, twice a day for 2 weeks followed by a 1-week rest. RESULTS Twenty-five patients were enrolled from July 2011 to June 2014. Three patients achieved PR, and 11 showed SD. The overall response rate was 12 %, and disease control rate was 56 %. With a median follow-up of 6.8 months, the median time to progression was 2.8 months and the median overall survival was 7.1 months. The most common non-hematologic toxicity was hand-foot syndrome (40 %), followed by mucositis (28 %) and diarrhea (12 %). Grade 3 hand-foot syndrome occurred in two patients (8 %), and grade 3 mucositis in one. Hematologic toxicities were mild, and only one patient developed grade 3 thrombocytopenia. CONCLUSION The combination of capecitabine and oral LV showed a modest activity and tolerable toxicity profile in metastatic CRC patients pretreated with irinotecan- and oxaliplatin-containing regimens. Oral LV seems to be able to reduce the usual dose of capecitabine when the two drugs are combined.
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Affiliation(s)
- Dae Ro Choi
- Division of Hemato-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Shingilro1, Youngdeungpo-Gu, Seoul, 150-950, Republic of Korea
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Figueiredo Junior AGD, Forones NM. Study on adherence to capecitabine among patients with colorectal cancer and metastatic breast cancer. ARQUIVOS DE GASTROENTEROLOGIA 2015; 51:186-91. [PMID: 25296077 DOI: 10.1590/s0004-28032014000300004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 04/14/2014] [Indexed: 11/22/2022]
Abstract
CONTEXT Capecitabine, an oral drug, is as effective as traditional chemotherapy drugs. OBJECTIVES To investigate the adhesion to treatment with oral capecitabine in breast and colorectal cancer, and to determine any correlation with changes in patient's quality of life. METHODS Patients with colorectal cancer or breast cancer using capecitabine were included. The patients were asked to bring any medication left at the time of scheduled visits. The QLQ-C30 questionnaire was applied at the first visit and 8-12 weeks after treatment. RESULTS Thirty patients were evaluated. Adherence was 88.3% for metastatic colon cancer, 90.4% for non-metastatic colon cancer, 94.3% for rectal cancer and 96.2% for metastatic breast cancer. No strong correlation between adherence and European Organisation for Research and Treatment of Cancer QLQ-C30 functional or symptom scale rates had been found. There was no statistically significant correlation between compliance and the functional and symptom scales of the questionnaire before and after chemotherapy, with the exception of dyspnea. CONCLUSIONS Although no absolute adherence to oral capecitabine treatment had been observed, the level of adherence was good. Health professionals therefore need a greater focus in the monitoring the involvement of patients with oral treatment regimens. Patients with lesser degrees of dyspnea had greater compliance.
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Affiliation(s)
| | - Nora Manoukian Forones
- Setor de Oncologia, Disciplina de Gastroenterologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil
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Li W, Xu J, Shen L, Liu T, Guo W, Zhang W, Chen Z, Zhu X, Li J. Phase II study of weekly irinotecan and capecitabine treatment in metastatic colorectal cancer patients. BMC Cancer 2014; 14:986. [PMID: 25527007 PMCID: PMC4300831 DOI: 10.1186/1471-2407-14-986] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 12/16/2014] [Indexed: 02/04/2023] Open
Abstract
Background The purpose of this phase II study was to evaluate the safety and efficacy of weekly irinotecan and capecitabine (wXELIRI) treatment in patients with metastatic colorectal cancer, specifically the rate of severe diarrhea. Methods Patients with unresectable histologically confirmed metastatic colorectal cancer with measurable disease received weekly irinotecan 90 mg/m2 on day 1 and capecitabine 1200 mg/m2 twice daily on days 1–5. Patients naïve to systemic chemotherapy for metastatic disease or who had failed FOLFOX (infusional 5-fluorouracil [5-FU], leucovorin, and oxaliplatin) or XELOX (capecitabine plus oxaliplatin) as first-line treatment were eligible. The primary endpoint was the rate of grade 3/4 diarrhea. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results A total of 52 patients were enrolled, 30 of whom received wXELIRI as first-line treatment and 22 as second-line treatment. Grade 4 diarrhea was observed in one patient and the rate of grade 3/4 diarrhea was 7.7%. The other common grade 3/4 toxicities included leukopenia (9.6%), neutropenia (17.3%), nausea (3.8%), vomiting (3.8%), fatigue (1.9%), and hand-foot syndrome (1.9%). The median progression-free survival and overall survival for the 30 patients treated in the first-line setting was 8.5 and 16.3 months, while those for the 22 patients treated in the second-line setting was 5.0 and 10.7 months, respectively. Conclusions The wXELIRI regimen resulted in a low rate of severe diarrhea with an acceptable toxicity profile. This study provides a basis for a subsequent randomized controlled study of wXELIRI versus FOLFIRI (irinotecan, 5-FU, and folinic acid) to further explore the efficacy and safety of this regimen. Trial registration ClinicalTrials.gov: NCT01322152.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jin Li
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China.
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Su M, Zhu LC, Wei HP, Luo WH, Lin RF, Zou CL. S-1-Based versus capecitabine-based preoperative chemoradiotherapy in the treatment of locally advanced rectal cancer: a matched-pair analysis. PLoS One 2014; 9:e106162. [PMID: 25181318 PMCID: PMC4152119 DOI: 10.1371/journal.pone.0106162] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2014] [Accepted: 07/28/2014] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE The aim of this paper was to compare the efficacy and safety of S-1-based and capecitabine-based preoperative chemoradiotherapy regimens in patients with locally advanced rectal cancer through a retrospective matched-pair analysis. MATERIALS AND METHODS Between Jan 2010 and Mar 2014, 24 patients with locally advanced rectal cancer who received preoperative radiotherapy concurrently with S-1 were individually matched with 24 contemporary patients with locally advanced rectal cancer who received preoperative radiotherapy concurrently with capecitabine according to clinical stage (as determined by pelvic magnetic resonance imaging and computed tomography) and age (within five years). All these patients performed mesorectal excision 4-8 weeks after the completion of chemoradiotherapy. RESULTS The tumor volume reduction rates were 55.9±15.1% in the S-1 group and 53.8±16.0% in the capecitabine group (p = 0.619). The overall downstaging, including both T downstaging and N downstaging, occurred in 83.3% of the S-1 group and 70.8% of the capecitabine group (p = 0.508). The significant tumor regression, including regression grade I and II, occurred in 33.3% of S-1 patients and 25.0% of capecitabine patients (p = 0.754). In the two groups, Grade 4 adverse events were not observed and Grade 3 consisted of only two cases of diarrhea, and no patient suffered hematologic adverse event of Grade 2 or higher. However, the incidence of diarrhea (62.5% vs 33.3%, p = 0.014) and hand-foot syndrome (29.2% vs 0%, p = 0.016) were higher in capecitabine group. Other adverse events did not differ significantly between two groups. CONCLUSIONS The two preoperative chemoradiotherapy regimens were effective and safe for patients of locally advanced rectal cancer, but regimen with S-1 exhibited a lower incidence of adverse events.
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Affiliation(s)
- Meng Su
- Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lu-Cheng Zhu
- Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hang-Ping Wei
- Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen-Hua Luo
- Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Rui-Fang Lin
- Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chang-Lin Zou
- Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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