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Zanni S, Del Prete J, Capogrossi A, Papapietro G, Del Cimmuto A, Gazzanelli S, Caronna A, Protano C. Influence of cigarette smoking on drugs' metabolism and effects: a systematic review. Eur J Clin Pharmacol 2025; 81:667-695. [PMID: 40111454 PMCID: PMC12003457 DOI: 10.1007/s00228-025-03817-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 02/23/2025] [Indexed: 03/22/2025]
Abstract
PURPOSE Cigarette smoke continues to be widely used around the world and it contains several substances that can affect the pharmacokinetics and/or pharmacodynamics of medications, altering their safety and effectiveness. The aim of this systematic review was to summarize the scientific evidence regarding possible changes in the pharmacokinetics and/or pharmacodynamics of drugs induced by cigarette smoking, possible mechanisms of action and related effects. METHODS The systematic review was performed according to the PRISMA Statement and the protocol was registered on the PROSPERO platform (CRD42023477784). Pubmed, Scopus, Web of Science databases were used. We considered observational, semi-experimental or experimental studies written in English and published between January 1, 2000, and November 13, 2024, focused on smoking subjects (healthy volunteers or patients) receiving any kind of medication. Data regarding possible modifications in drugs' pharmacokinetics and/or pharmacodynamics induced by cigarette smoking were assessed. The quality of observational studies and experimental studies was evaluated using the Newcastle-Ottawa Quality Assessment Scale and the Jadad Scale, respectively. RESULTS In total, 37 studies were included, and 31 of them showed relevant modifications in the pharmacokinetics or effects of the drugs in smokers compared to non-smokers. Most of the included studies (n = 20) investigated drugs for psychiatric or neurological disorders, showing a reduction in plasma concentration or an increase in drug clearance in smokers as well as antibiotics metronidazole and cycloserine. Besides, seven articles focused on anticancer drugs indicating an increase in drug metabolism. The remaining articles reported effects of smoking on the metabolism of other drugs, such as cardiovascular drugs, phosphodiesterase 5 inhibitors, local anesthetics and medications for musculoskeletal or chronic obstructive pulmonary diseases. Induction of the cytochrome enzyme CYP1A2 is the most common mechanism mediating the reduction of drug concentrations by cigarette smoking. CONCLUSION The results indicate an increased risk of therapeutic failure for smokers and represent further motivation to encourage smoking cessation or attention in formulating personalized therapy.
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Affiliation(s)
- Stefano Zanni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy
| | - Jole Del Prete
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy
| | - Alessandra Capogrossi
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy
| | - Giuseppe Papapietro
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy
| | - Angela Del Cimmuto
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy
| | - Sergio Gazzanelli
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy
| | - Andrea Caronna
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy
| | - Carmela Protano
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, P.Le Aldo Moro 5, 00185, Rome, Italy.
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Saito Y, Takekuma Y, Komatsu Y, Sugawara M. Impact of renal impairment on early development of severe neutropenia with trifluridine/tipiracil treatment for metastatic colorectal cancer. Sci Rep 2024; 14:26990. [PMID: 39506021 PMCID: PMC11541766 DOI: 10.1038/s41598-024-78741-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 11/04/2024] [Indexed: 11/08/2024] Open
Abstract
Trifluridine/tipiracil (FTD/TPI) with or without bevacizumab is an effective treatment for metastatic colorectal cancer (mCRC). As this agent is mainly excreted via the kidney, we aimed to evaluate the impact of renal impairment (RI) on the early development of severe neutropenia, a dose-limiting toxicity and whose development reflects better treatment outcomes, in patients with mCRC treated with FTD/TPI. Patients with mCRC receiving FTD/TPI ± bevacizumab (n = 100) were divided into the RI group (creatinine clearance [CCr] < 90 mL/min) or control group (CCr ≥ 90 mL/min), and retrospectively evaluated. Severe neutropenia during the first two cycles occurred in 57.6% and 34.2% of patients in the RI and control groups, respectively, which was significantly different (P = 0.03) and met our primary endpoint. Furthermore, the incidence during the first cycle also differed significantly (52.5% in the RI group and 17.1% in the control group, P = 0.0004). Multivariate logistic regression analysis suggested that baseline RI and neutropenia were significant risk factors for early severe neutropenia (adjusted odds ratio and 95% confidence interval: 3.07, 1.24-7.59, P = 0.02 for RI, and 9.76, 1.08-88.11, P = 0.04 for neutropenia). In conclusion, our study suggested that patients with RI can exhibit early severe neutropenia during real-world FTD/TPI treatment for mCRC.
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Affiliation(s)
- Yoshitaka Saito
- Department of Clinical Pharmaceutics & Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 4-1, Maeda 7-jo 15-chome, Teine-ku, Sapporo, 006-8585, Japan.
| | - Yoh Takekuma
- Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan
| | - Yoshito Komatsu
- Cancer Center, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan
| | - Mitsuru Sugawara
- Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan
- Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo, 060-0812, Japan
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Chandasana H, Bush M, Ait-Khaled M, Wynne B, Min S, Mehta R. Population Pharmacokinetic Analysis of Dolutegravir in Treatment-Experienced Adults Living with HIV-1. J Clin Pharmacol 2024; 64:1407-1418. [PMID: 39011960 DOI: 10.1002/jcph.2494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 06/06/2024] [Indexed: 07/17/2024]
Abstract
The World Health Organization has recommended the use of dolutegravir (DTG) for both first and second-line antiretroviral treatment in both adults and children down to 4 weeks of age. We developed a population pharmacokinetic(PopPK) model following oral administration of DTG 50 mg QD and 50 mg BID in HIV-infected treatment-experienced adults (607) based on pooled data from four phase 2/3 trials. DTG population pharmacokinetics are described by a one-compartment model with first-order absorption, absorption lag-time, and first-order elimination. The PopPK parameter estimates were apparent oral clearance (CL/F) = 1.00 L/h, apparent volume of distribution (V/F) = 18.9 L, absorption rate constant (Ka) = 1.99 per hour, and absorption lag time = 0.333 h, respectively. The final model included inter-individual and inter-occasion variability on apparent clearance (CL/F). Weight, smoking status, use of metabolic inducers as part of background antiretroviral therapy (ART) classified by their level of induction, use of atazanavir or atazanavir-ritonavir as part of background ART, and albumin level were predictors of CL/F; weight and albumin level were predictors of V/F; and sex and concomitant use of metal cation-containing vitamin/mineral supplements were predictors of relative bioavailability (F). The current model-based analysis suggests that the DTG dose adjustment is not required based on the demographics, laboratory values, smoking status, concomitant use of mild metabolic inducers or inhibitors in the background therapy, or use of metal cation-containing vitamin/mineral supplements because these covariate effects are not predicted to have a clinically relevant impact on safety and efficacy.
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Leonhardt CS, Pils D, Qadan M, Gustorff C, Sahora K, Klaiber U, Warshaw AL, Prager G, Ferrone CR, Lillemoe KD, Schindl M, Strobel O, Castillo CFD, Hank T. Smoking impairs the effect of neoadjuvant FOLFIRINOX on postresection survival in pancreatic cancer. Eur J Cancer 2023; 193:113293. [PMID: 37713740 DOI: 10.1016/j.ejca.2023.113293] [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: 08/05/2023] [Accepted: 08/10/2023] [Indexed: 09/17/2023]
Abstract
INTRODUCTION Smoking plays an important role in carcinogenesis, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the association between smoking status and prognosis in resected PDAC. METHODS All patients who underwent resection for PDAC were identified from two prospective institutional databases. Clinicopathologic data as well as demographics including smoking status were extracted. Survival analysis and multivariable Cox regression modelling was performed. Restricted cubic splines were used for linear data to define cut-off points. RESULTS Out of 848 patients, 357 (42.1%) received neoadjuvant treatment (NAT), 491 upfront resection (57.9%), and 475 (56%) adjuvant therapy. The median overall survival (OS) was 27.8 months, 36.1 months, and 23.0 months for the entire cohort, after NAT and upfront resection. 464 patients were never smokers (54.7%), 250 former smokers (29.5%), and 134 active smokers (15.8%). In the multivariable model, the interaction of neoadjuvant FOLFIRINOX and active smoking was associated with the highest risk for decreased OS (harzard ratio (HR) 2.35; 95% confidence interval 1.13-4.90) and strongly mitigated the benefit of FOLFIRNOX (HR 0.40; 95% CI 0.25-0.63). Adjusted median OS in NAT patients with FOLFIRINOX was not reached for never and former smokers, compared to 26.2 months in active smokers. Based on the model, a nomogram was generated to illustrate the probability of 5-year survival after PDAC resection. CONCLUSION The present study confirms that neoadjuvant FOLFIRINOX is associated with excellent survival and demonstrates that active smoking reduces its benefit. The nomogram can assist in daily clinical practice and emphasises the importance of smoking cessation in patients with PDAC, especially prior to NAT with FOLFIRINOX.
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Affiliation(s)
- Carl-Stephan Leonhardt
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Dietmar Pils
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Motaz Qadan
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Charlotte Gustorff
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Klaus Sahora
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Ulla Klaiber
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Andrew L Warshaw
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Gerald Prager
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Martin Schindl
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Oliver Strobel
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | | | - Thomas Hank
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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Zhao Q, Chen Y, Huang W, Zhou H, Zhang W. Drug-microbiota interactions: an emerging priority for precision medicine. Signal Transduct Target Ther 2023; 8:386. [PMID: 37806986 PMCID: PMC10560686 DOI: 10.1038/s41392-023-01619-w] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 07/20/2023] [Accepted: 08/24/2023] [Indexed: 10/10/2023] Open
Abstract
Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.
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Affiliation(s)
- Qing Zhao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, PR China
| | - Yao Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, PR China
| | - Weihua Huang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, PR China
| | - Honghao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China
- National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, PR China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China.
- The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, PR China.
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, PR China.
- Central Laboratory of Hunan Cancer Hospital, Central South University, 283 Tongzipo Road, Changsha, 410013, PR China.
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Zhang S, Yang J, Zhan H, Yang B, Rong P, Luo Y, Shi C, Chen Y, Yang J. Incidence and non-genetic risk factors of irinotecan-induced severe neutropenia in Chinese adult inpatients. Medicine (Baltimore) 2023; 102:e33005. [PMID: 36862924 PMCID: PMC9981354 DOI: 10.1097/md.0000000000033005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/04/2023] Open
Abstract
To analyze the incidence and nongenetic risk factors of irinotecan-induced severe neutropenia in the hospital, and provide additional reference and help for clinical treatment. A retrospective analysis of patients who received irinotecan based chemotherapy from May 2014 to May 2019 in Renmin Hospital of Wuhan University was conducted. Univariate analysis and binary logistic regression analysis with the forward stepwise method were used to assess the risk factors associated with severe neutropenia induced by irinotecan. Of the 1312 patients treated with irinotecan-based regmines, only 612 patients met the inclusion criteria, and 32 patients developed irinotecan-induced severe neutropenia. In the univariate analysis, variables associated with severe neutropenia were tumor type, tumor stage, and therapeutic regimen. In the multivariate analysis, irinotecan plus lobaplatin, lung cancer or ovarian cancer, tumor stage T2, T3, and T4, were identified as risk factors that contributed independently to irinotecan-induced severe neutropenia (P < .05), respectively. The results showed that the incidence of irinotecan-induced severe neutropenia was 5.23% in the hospital. The risk factors included tumor type (lung cancer or ovarian cancer), tumor stage (T2, T3, and T4) and therapeutic regimen (irinotecan plus lobaplatin). Therefore, for patients with these risk factors, it might be advisable to actively consider optimum management to reduce the occurrence of irinotecan-induced severe neutropenia.
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Affiliation(s)
- Shuxiao Zhang
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - JingXiang Yang
- Department of Pharmacy, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Haiyan Zhan
- Department of Pharmacy, Wuhan Jinyintan Hospital, Wuhan, China
| | - Boning Yang
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - PeiPei Rong
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yi Luo
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Cai Shi
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ying Chen
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jian Yang
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
- * Correspondence: Jian Yang, Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China (e-mail: )
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Eng L, Brual J, Nagee A, Mok S, Fazelzad R, Chaiton M, Saunders DP, Mittmann N, Truscott R, Liu G, Bradbury PA, Evans WK, Papadakos J, Giuliani ME. Reporting of tobacco use and tobacco-related analyses in cancer cooperative group clinical trials: a systematic scoping review. ESMO Open 2022; 7:100605. [PMID: 36356412 PMCID: PMC9646674 DOI: 10.1016/j.esmoop.2022.100605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/21/2022] [Accepted: 09/23/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Continued smoking after a diagnosis of cancer negatively impacts cancer outcomes, but the impact of tobacco on newer treatments options is not well established. Collecting and evaluating tobacco use in clinical trials may advance understanding of the consequences of tobacco use on treatment modalities, but little is known about the frequency of reporting and analysis of tobacco use in cancer cooperative clinical trial groups. PATIENTS AND METHODS A comprehensive literature search was conducted to identify cancer cooperative group clinical trials published from January 2017-October 2019. Eligible studies evaluated either systemic and/or radiation therapies, included ≥100 adult patients, and reported on at least one of: overall survival, disease/progression-free survival, response rates, toxicities/adverse events, or quality-of-life. RESULTS A total of 91 studies representing 90 trials met inclusion criteria with trial start dates ranging from 1995 to 2015 with 14% involving lung and 5% head and neck cancer patients. A total of 19 studies reported baseline tobacco use; 2 reported collecting follow-up tobacco use. Seven studies reported analysis of the impact of baseline tobacco use on clinical outcomes. There was significant heterogeneity in the reporting of baseline tobacco use: 7 reported never/ever status, 10 reported never/ex-smoker/current smoker status, and 4 reported measuring smoking intensity. None reported verifying smoking status or second-hand smoke exposure. Trials of lung and head and neck cancers were more likely to report baseline tobacco use than other disease sites (83% versus 6%, P < 0.001). CONCLUSIONS Few cancer cooperative group clinical trials report and analyze trial participants' tobacco use. Significant heterogeneity exists in reporting tobacco use. Routine standardized collection and reporting of tobacco use at baseline and follow-up in clinical trials should be implemented to enable investigators to evaluate the impact of tobacco use on new cancer therapies.
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Affiliation(s)
- L Eng
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada.
| | - J Brual
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - A Nagee
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - S Mok
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - R Fazelzad
- Library and Information Services, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - M Chaiton
- Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
| | - D P Saunders
- Northeast Cancer Centre of Health Sciences North, Northern Ontario School of Medicine, Sudbury, Canada
| | - N Mittmann
- Canadian Agency for Drugs and Technologies in Health, Toronto, Canada
| | - R Truscott
- Division of Prevention Policy and Stakeholder Engagement, Ontario Health (Cancer Care Ontario), Toronto, Canada
| | - G Liu
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada
| | - P A Bradbury
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada
| | - W K Evans
- Department of Oncology, McMaster University, Hamilton, Canada
| | - J Papadakos
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada; Patient Education, Ontario Health (Cancer Care Ontario), Toronto, Canada
| | - M E Giuliani
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada; Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Canada.
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Han K, Baker M, Lovern M, Paul P, Xiong Y, Patel P, Moore KP, Seal CS, Cutrell AG, D'Amico RD, Benn PD, Landovitz RJ, Marzinke MA, Spreen WR, Ford SL. Population pharmacokinetics of cabotegravir following administration of oral tablet and long-acting intramuscular injection in adult HIV-1-infected and uninfected subjects. Br J Clin Pharmacol 2022; 88:4607-4622. [PMID: 35695476 PMCID: PMC9543358 DOI: 10.1111/bcp.15439] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 05/16/2022] [Accepted: 05/21/2022] [Indexed: 11/29/2022] Open
Abstract
AIM To characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability. METHODS Analyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood-based approaches. Covariate relationships were evaluated using forward addition (P < .01) and backward elimination (P < .001) approaches. The impact of each covariate on trough and peak concentrations was evaluated through simulations. External validation was performed using prediction-corrected visual predictive checks. RESULTS The model-building dataset included 23 926 plasma concentrations from 1647 adult HIV-1-infected (72%) and uninfected (28%) subjects in 16 studies at seven dose levels (oral 10-60 mg, long-acting [LA] intramuscular injection 200-800 mg). A two-compartment model with first-order oral and LA absorption and elimination adequately described the data. Clearances and volumes were scaled to body weight. Estimated relative bioavailability of oral to LA was 75.6%. Race and age were not significant covariates. LA absorption rate constant (KALA ) was 50.9% lower in females and 47.8% higher if the LA dose was given as two split injections. KALA decreased with increasing BMI and decreasing needle length. Clearance was 17.4% higher in current smokers. The impact of any covariate was ≤32% on trough and peak concentrations following LA administration. The final model adequately predicted 5097 plasma concentrations from 647 subjects who were not included in the model-building dataset. CONCLUSIONS A cabotegravir population pharmacokinetic model was developed that can be used to inform dosing strategies and future study design. No dose adjustment based on subject covariates is recommended.
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Affiliation(s)
| | - Mark Baker
- ViiV HealthcareResearch Triangle ParkNCUSA
| | - Mark Lovern
- Certara Consulting ServicesResearch Triangle ParkNCUSA
| | - Prokash Paul
- Certara Consulting ServicesResearch Triangle ParkNCUSA
| | | | | | | | | | | | | | | | - Raphael J. Landovitz
- UCLA Center for Clinical AIDS Research & EducationUniversity of CaliforniaLos AngelesCAUSA
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Corke LK, Li JJN, Leighl NB, Eng L. Tobacco Use and Response to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer. Curr Oncol 2022; 29:6260-6276. [PMID: 36135061 PMCID: PMC9498279 DOI: 10.3390/curroncol29090492] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
Tobacco is a known risk factor for lung cancer, and continued tobacco use is associated with poorer outcomes across multiple lung cancer treatment modalities including surgery, chemotherapy and radiation therapy. Less is known about the association of tobacco use and outcomes with immune checkpoint inhibitors (ICIs), which are becoming an important part of the treatment landscape in lung cancer, both in metastatic and curative settings. We reviewed the literature on the association of tobacco and tumor biology as it relates to immunotherapy. We also reviewed the association of tobacco use on outcomes among phase III randomized clinical trials involving ICIs in non-small cell lung cancer (NSCLC). We identified that patients with a smoking history may have a greater benefit with ICI treatment compared to never smokers in both treatment-naïve (HR 0.82, 95% CI 0.69-0.97, vs. HR 1.06, 95% CI 0.81-1.38) and pre-treated (HR 0.79, 95% CI 0.70-0.90 vs. 1.03, 95% CI 0.74-1.43) settings. In trials where smoking status was further defined, ex-smokers appear to demonstrate greater benefit with ICI therapy compared to current smokers (HR 0.78, 95% CI 0.59-1.01 vs. 0.91, 95% CI 0.72-1.14). We conclude by offering our perspective on future directions in this area of research, including implementation of standardized collection and analysis of tobacco use in clinical trials involving ICI therapy in lung cancer and other disease sites, and also evaluating how tobacco may affect toxicities related to ICI therapy. Based on our review, we believe that a patient's history of tobacco smoking does have a role to play in guiding treatment decision making in patients with lung cancer.
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Affiliation(s)
- Lucy K. Corke
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network Toronto, Toronto, ON M5G 2C1, Canada
- Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Janice J. N. Li
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network Toronto, Toronto, ON M5G 2C1, Canada
- Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Natasha B. Leighl
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network Toronto, Toronto, ON M5G 2C1, Canada
- Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Lawson Eng
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, University Health Network Toronto, Toronto, ON M5G 2C1, Canada
- Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
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10
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Wang T, Read SH, Moino D, Ayoubi Y, Chern JY, Tworoger SS. Tobacco Smoking and Survival Following a Diagnosis with Ovarian Cancer. Cancer Epidemiol Biomarkers Prev 2022; 31:1376-1382. [PMID: 35775222 DOI: 10.1158/1055-9965.epi-21-1327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/01/2022] [Accepted: 04/27/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Little is known about the influence of smoking on ovarian cancer survival. We investigated this relationship in a hospital-based study. METHODS Analyses included 519 women with ovarian cancer. We used multivariable adjusted Cox proportional hazards regression models to estimate HRs and 95% confidence intervals (CI). RESULTS Risk of all-cause mortality was increased for current smokers (HR = 1.70; 95% CI: 1.09-2.63) versus never smokers, especially for those with ≥15 cigarettes per day (HR = 1.92; 95% CI: 1.15-3.20). Results were largely similar after additional adjustment for debulking status (current vs. never smokers, HR = 2.96; 95% CI: 1.07-8.21) or neoadjuvant chemotherapy (comparable HR = 2.87; 95% CI: 1.02-8.06). Compared with never smokers, smoking duration ≥20 years (HR = 1.38; 95% CI: 0.94-2.03) and ≥20 pack-years (HR = 1.35; 95% CI: 0.92-1.99) were suggestively associated with worse outcomes. Current smoking was also positively associated with the risk of mortality among patients with ovarian cancer recurrence (current vs. never/past smokers, HR = 2.79; 95% CI: 1.44-5.41), despite the null association between smoking and recurrence (HR = 1.46; 95% CI: 0.86-2.48). Furthermore, no association was observed for smoking initiation before age 18 (HR = 1.22; 95% CI: 0.80-1.85), or either environmental smoke exposure at home (HR = 1.16; 95% CI: 0.76-1.78) or at work (HR = 1.10; 95% CI: 0.75-1.60). CONCLUSIONS Our results suggest active tobacco smoking is associated with worse ovarian cancer outcomes, particularly after a recurrence. IMPACT Our findings support structured smoking cessation programs for patients with ovarian cancer, especially in recurrent settings. Further research to confirm these findings and examine the interplay between smoking and the tumor immune microenvironment may help provide insight into ovarian cancer etiology.
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Affiliation(s)
- Tianyi Wang
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Susan H Read
- Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.,Morsani College of Medicine, University of South Florida, Tampa, Florida
| | - Daniela Moino
- Morsani College of Medicine, University of South Florida, Tampa, Florida
| | - Yasmin Ayoubi
- Morsani College of Medicine, University of South Florida, Tampa, Florida
| | - Jing-Yi Chern
- Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Shelley S Tworoger
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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11
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Drug Resistance in Colorectal Cancer: From Mechanism to Clinic. Cancers (Basel) 2022; 14:cancers14122928. [PMID: 35740594 PMCID: PMC9221177 DOI: 10.3390/cancers14122928] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
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12
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Integration of DNA sequencing with population pharmacokinetics to improve the prediction of irinotecan exposure in cancer patients. Br J Cancer 2021; 126:640-651. [PMID: 34703007 DOI: 10.1038/s41416-021-01589-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Irinotecan (CPT-11) is an anticancer agent widely used to treat adult solid tumours. Large interindividual variability in the clearance of irinotecan and SN-38, its active and toxic metabolite, results in highly unpredictable toxicity. METHODS In 217 cancer patients treated with intravenous irinotecan single agent or in combination, germline DNA was used to interrogate the variation in 84 genes by next-generation sequencing. A stepwise analytical framework including a population pharmacokinetic model with SNP- and gene-based testing was used to identify demographic/clinical/genetic factors that influence the clearance of irinotecan and SN-38. RESULTS Irinotecan clearance was influenced by rs4149057 in SLCO1B1, body surface area, and co-administration of 5-fluorouracil/leucovorin/bevacizumab. SN-38 clearance was influenced by rs887829 in UGT1A1, pre-treatment total bilirubin, and EGFR rare variant burden. Within each UGT1A1 genotype group, elevated pre-treatment total bilirubin and/or presence of at least one rare variant in EGFR resulted in significantly lower SN-38 clearance. The model reduced the interindividual variability in irinotecan clearance from 38 to 34% and SN-38 clearance from 49 to 32%. CONCLUSIONS This new model significantly reduced the interindividual variability in the clearance of irinotecan and SN-38. New genetic factors of variability in clearance have been identified.
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13
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Michael M, Liauw W, McLachlan SA, Link E, Matera A, Thompson M, Jefford M, Hicks RJ, Cullinane C, Hatzimihalis A, Campbell IG, Rowley S, Beale PJ, Karapetis CS, Price T, Burge ME. Pharmacogenomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: the predict IR study. Cancer Chemother Pharmacol 2021; 88:39-52. [PMID: 33755789 DOI: 10.1007/s00280-021-04264-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/16/2021] [Indexed: 11/25/2022]
Abstract
PURPOSE Irinotecan (IR) displays significant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response). METHODS Eligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Affymetrix-DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250 MBq-99mTc-IDA, data derived for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS). RESULTS N = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P < 0.05) included: (1) PK: SN38-Metabolic Ratio with CLHNI, 1hRET, (2) Grade 3+ diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+ neutropenia with CLHNI, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T1/2-HNI, XDH (rs 207440), and ABCB11 (rs 4148777). CONCLUSIONS Exploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extensive pharmacogenomics. Further work is required to confirm and validate these findings in a larger cohort of patients. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY (ANZCTR) NUMBER ACTRN12610000897066, Date registered: 21/10/2010.
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Affiliation(s)
- Michael Michael
- Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
| | - Winston Liauw
- Department of Medical Oncology, St. George's Hospital, Sydney, Australia
| | - Sue-Anne McLachlan
- Department of Medical Oncology, St. Vincent's Hospital, Melbourne, Australia
| | - Emma Link
- Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Annetta Matera
- Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Michael Thompson
- Division of Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Michael Jefford
- Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia
| | - Rod J Hicks
- Division of Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Carleen Cullinane
- Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Athena Hatzimihalis
- Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Ian G Campbell
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Simone Rowley
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Phillip J Beale
- Department of Medical Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Christos S Karapetis
- Department of Medical Oncology, Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Adelaide, Australia
| | - Timothy Price
- Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia
| | - Mathew E Burge
- Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Australia
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14
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The characteristics of patients who quit smoking in the year following a cancer diagnosis. J Cancer Surviv 2021; 16:111-118. [PMID: 33641030 PMCID: PMC10117081 DOI: 10.1007/s11764-021-01009-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/17/2021] [Indexed: 10/22/2022]
Abstract
PURPOSE Continued tobacco smoking following a cancer diagnosis is associated with adverse outcomes. Our study aims to identify the demographic and clinical characteristics of survivors who quit smoking within a year of diagnosis. METHODS We conducted a secondary analysis of the Measuring Your Health (MY-Health) study, a community-based survey cohort of 5506 cancer patients registered across four Surveillance, Epidemiology, and End Results (SEER) cancer registries. Using surveys completed 6-13 months after diagnosis, we identified 868 participants who reported smoking around the time of cancer diagnosis and compared their current smoking status. We employed logistic regression models to predict current smoking status, adjusting for clinical and demographic variables. RESULTS The overall smoking cessation rate was 35% (n = 306). Survivors with non-small cell lung cancer were three times more likely to quit smoking compared to patients with non-smoking-related cancers (aOR = 3.23, 95% CI = 2.20-4.74). Participants with advanced stage cancer reported higher odds of quitting compared to those with localized cancer (aOR = 1.42, 95% CI = 1.02-1.96). Other characteristics that predicted quitting included being married, higher education level, and female sex (aOR = 2.01, 95% CI = 1.46-2.77; aOR = 1.74, 95% CI = 1.27-2.39; aOR = 1.54, 95% CI = 1.11-2.13, respectively). CONCLUSIONS This is one of the first studies to examine smoking cessation trends in a community-based, US cancer cohort during the year after diagnosis. Survivors with lung cancer and advanced cancer were significantly more likely to quit smoking. IMPLICATIONS FOR CANCER SURVIVORS Practitioners may use this knowledge to target interventions and address substantial disparities in cessation rates among survivors with early stage and non-lung cancers.
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15
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Saito Y, Takekuma Y, Kobayashi M, Komatsu Y, Sugawara M. Detection of risk factors related to administration suspension and severe neutropenia in gemcitabine and nab-paclitaxel treatment. Support Care Cancer 2020; 29:3277-3285. [PMID: 33104920 DOI: 10.1007/s00520-020-05842-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE The combination of gemcitabine (GEM) and nanoparticle albumin-bound paclitaxel (nab-PTX) is an effective chemotherapeutic regimen for locally advanced and metastatic pancreatic cancer. The dose-limiting toxicities (DLTs) of this treatment are sepsis and neutropenia, while the relative dose intensity (RDI) of GEM is approximately 75% and of nab-PTX is 70-80%. In this study, we evaluated the risk factor(s) regarding treatment suspension, which leads to reduction in the RDI of these agents, enabling appropriate schedule management. METHODS Two hundred patients with pancreatic cancer who received GEM + nab-PTX were retrospectively investigated. Frequency and risk factor(s) of suspension of the treatment and grade 3/4 neutropenia in the first course were evaluated. RESULTS The frequency of treatment suspension in the first course was 61%. The frequency of grade 3/4 neutropenia was 51%, while that of thrombocytopenia was 7.5%. The RDI was 78.0% for GEM and 77.7% for nab-PTX. Univariate and multivariate analyses to identify risk or preventive factors related to treatment suspension suggested that low platelet count at baseline was a risk factor, whereas dose reduction from the treatment initiation was a preventive factor. The most common cause of abeyance was grade 3/4 neutropenia (83.6%), the risk factors of which were low platelet count and age ≥ 65 years at baseline, while dose reduction was a preventive factor. CONCLUSION We found that a low platelet level at baseline was a risk factor, whereas dose reduction from initiation was a preventive factor in regard to treatment suspension and severe neutropenia occurrence in GEM + nab-PTX treatment.
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Affiliation(s)
- Yoshitaka Saito
- Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan
| | - Yoh Takekuma
- Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan
| | - Masaki Kobayashi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo, 060-0812, Japan
| | - Yoshito Komatsu
- Cancer Center, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan
| | - Mitsuru Sugawara
- Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan. .,Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo, 060-0812, Japan.
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16
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Kodal JB, Çolak Y, Kobylecki CJ, Vedel-Krogh S, Nordestgaard BG, Afzal S. Smoking Reduces Plasma Bilirubin: Observational and Genetic Analyses in the Copenhagen General Population Study. Nicotine Tob Res 2020; 22:104-110. [PMID: 30202916 DOI: 10.1093/ntr/nty188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 09/05/2018] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Observational studies have found lower concentrations of plasma bilirubin in current smokers compared with former and never smokers. However, whether there is a causal relationship between smoking and bilirubin is unknown. In a Mendelian randomization analysis, we tested the hypothesis that higher tobacco consumption is causally associated with lower concentrations of plasma bilirubin. METHODS We genotyped 103 557 individuals aged 20-100 years from the Copenhagen General Population Study for the CHRNA3 rs1051730 genotype, known to be associated with higher tobacco consumption. Tobacco consumption was defined as daily and cumulative tobacco consumption. RESULTS In observational multivariable-adjusted analyses, a 10 g/day higher daily tobacco consumption was associated with a 0.28 µmol/L (95% confidence interval = 0.20 to 0.35) lower concentration of plasma bilirubin in current smokers, and a 10 pack-year higher cumulative tobacco consumption was associated with a 0.19 µmol/L (0.17 to 0.21) lower concentration of plasma bilirubin in former and current smokers. Using the CHRNA3 rs1051730 genotype as a proxy for daily and cumulative tobacco consumption, the difference in plasma bilirubin per T-allele was -0.12 µmol/L (-0.23 to -0.002) in current smokers and -0.09 µmol/L (-0.15 to -0.01) in current and former smokers combined. Furthermore, observationally bilirubin concentrations increased with time from smoking cessation in former smokers. CONCLUSION Higher daily and cumulative tobacco consumption were associated with lower concentrations of plasma bilirubin in observational and genetic analyses, suggesting that the association is causal. IMPLICATIONS Our results are compatible with two possible interpretations of previous observational studies, either that bilirubin is a mediator of smoking-induced respiratory disease or that the association between plasma bilirubin and respiratory disease stems from residual confounding because of smoking. Future studies should examine whether bilirubin is a causal risk factor for respiratory disease, or merely a marker of smoking status.
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Affiliation(s)
- Jakob B Kodal
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of clinical biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Yunus Çolak
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of clinical biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Camilla J Kobylecki
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of clinical biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Signe Vedel-Krogh
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of clinical biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of clinical biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Shoaib Afzal
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.,Department of clinical biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
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17
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Giuliani M, Brual J, Cameron E, Chaiton M, Eng L, Haque M, Liu G, Mittmann N, Papadakos J, Saunders D, Truscott R, Evans W. Smoking Cessation in Cancer Care: Myths, Presumptions and Implications for Practice. Clin Oncol (R Coll Radiol) 2020; 32:400-406. [PMID: 32029357 DOI: 10.1016/j.clon.2020.01.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/26/2019] [Accepted: 12/04/2019] [Indexed: 10/25/2022]
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18
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Perlík F. Impact of smoking on metabolic changes and effectiveness of drugs used for lung cancer. Cent Eur J Public Health 2020; 28:53-58. [PMID: 32228818 DOI: 10.21101/cejph.a5620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 11/17/2019] [Indexed: 11/15/2022]
Affiliation(s)
- František Perlík
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
- Institute for Postgraduate Medical Education, Prague, Czech Republic
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19
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Coovadia S, D'Alimonte L, Bristow B, Curle E, Gibson L, Di Prospero L. Catalyst for Change: Measuring the Effectiveness of Training of All Health Care Professionals to Provide Brief Intervention for Smoking Cessation to Cancer Patients. J Med Imaging Radiat Sci 2019; 51:7-11. [PMID: 31864933 DOI: 10.1016/j.jmir.2019.10.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/02/2019] [Accepted: 10/02/2019] [Indexed: 11/18/2022]
Abstract
BACKGROUND Smoking cessation is recommended to prevent individuals from developing cancer, with additional benefits after a cancer diagnosis. Tobacco use during cancer treatments increases the risk of complications and may reduce the effectiveness of treatment; patients who quit smoking are less likely to experience recurrence. Health care professionals play a vital role in assessing and educating cancer patients on how to quit. We report on the effectiveness of peer-to-peer education of a brief smoking cessation intervention to patients. METHODS An interprofessional team was created to implement and integrate smoking cessation best practices into daily clinical care. Health care providers were provided with peer-to-peer training to provide brief interventions of smoking cessation to patients. After training, participants were invited to complete an electronic survey to assess the effectiveness of the peer-to-peer training sessions. The survey consisted of 3 domains: confidence, comfort, and knowledge. Participants were asked to rate a series of statement questions using a Likert scale as well as to self-assess knowledge. The survey also included open-ended questions to invite respondents to share further comments and feedback. RESULTS Approximately 90% of staff across the oncology program participated in a training session. This included nurses, radiation therapists, and patient and family support professionals. Sixty-one surveys were returned (30% response rate). Most respondents had >10 years of clinical experience (70%), 91% agreed it was important to support patients in their efforts to quit smoking, 88% agreed they have an impact on their patients' smoking cessation attempts, and 67% had opportunities in daily practice to support smoking cessation. Sixty-one percent would benefit from additional education. Fifty-three percent indicated they experienced challenges providing interventions and patients' responsiveness to the intervention. CONCLUSIONS Peer-to-peer training for smoking cessation can increase confidence, comfort, and knowledge. Challenges include comfort level of clinician, determining the best time to ask patients, and having the confidence in knowing their scope of practice.
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Affiliation(s)
- Sadiya Coovadia
- Department of Radiation Therapy, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Laura D'Alimonte
- Department of Radiation Therapy, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Nursing, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Bonnie Bristow
- Department of Radiation Therapy, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Elaine Curle
- Department of Patient and Family Support, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Leslie Gibson
- Practice-based Research and Innovation, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Lisa Di Prospero
- Department of Nursing, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
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20
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Sakhri L, Bertocchi M. [Bronchial carcinoma and tobacco: An update]. Rev Mal Respir 2019; 36:1129-1138. [PMID: 31767264 DOI: 10.1016/j.rmr.2018.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 06/18/2018] [Indexed: 11/29/2022]
Abstract
Lung cancer remains the most lethal cancer. The most common cause is smoking, which is also preventable, unlike the causes of other types of cancer. A genetic characteristic has emerged over several years, which explains particular profiles of smokers, or highly dependent smokers. The emergence of new therapies for the treatment of lung cancer, and the impact of tobacco on reducing the effectiveness of these therapies must challenge practitioners to obtain a complete cessation of smoking regardless of the stage of the disease.
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Affiliation(s)
- L Sakhri
- Institut de cancérologie Daniel-Hollard, groupe hospitalier mutualiste de Grenoble, 8, rue Docteur-Calmette, 38028 Grenoble cedex 1, France.
| | - M Bertocchi
- Service de pneumologie, centre hospitalier Annecy Genevois, 1, avenue de l'Hôpital, 74374 Pringy, France
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21
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de Man FM, Goey AKL, van Schaik RHN, Mathijssen RHJ, Bins S. Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics. Clin Pharmacokinet 2019. [PMID: 29520731 PMCID: PMC6132501 DOI: 10.1007/s40262-018-0644-7] [Citation(s) in RCA: 270] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters could predict a part of the drug-related toxicity and efficacy of treatment, which has been shown in retrospective and prospective trials and meta-analyses. Patient characteristics, lifestyle and comedication also influence irinotecan pharmacokinetics. Other factors, including dietary restriction, are currently being studied. Meanwhile, a more tailored approach to prevent excessive toxicity and optimize efficacy is warranted. This review provides an updated overview on today’s literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics.
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Affiliation(s)
- Femke M de Man
- Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015, Rotterdam, The Netherlands
| | - Andrew K L Goey
- Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015, Rotterdam, The Netherlands
| | - Sander Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015, Rotterdam, The Netherlands.
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22
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Zhang M, Bao Y, Chen W, Wei M, Pang H, Ren YF, Mei J, Ye S, Fu S, Peng ZW. TBH score: a new model to predict and prevent severe liver damage after chemotherapy for cancer patients. Cancer Manag Res 2019; 11:6443-6456. [PMID: 31372047 PMCID: PMC6630723 DOI: 10.2147/cmar.s199967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 05/08/2019] [Indexed: 12/03/2022] Open
Abstract
Purpose To explore a quantitative predictive model for the risk of chemotherapy-induced severe liver damage (CISLD). Materials and methods In total, 3870 consecutive cancer patients initially treated with chemotherapy were retrospectively collected and randomly assigned to a training (n=2580) or internal validation (n=1290) set in a 2:1 ratio to construct and validate the model. Additional external validation was performed using another data set (n=413). A total of 486 patients were prospectively enrolled to assess the clinical significance of the model. CISLD was defined as grade ≥3 hepatotoxicity. Results CISLD was found in 255 (9.9%), 128 (9.9%) and 36 (8.7%) patients in the training, internal and external validation sets, respectively. Serum triglyceride, body mass index and history of hypertension formed the basis of the score model. Patients could be stratified into low, intermediate and high-risk groups with <10%, 10–30% and >30% CISLD occurrence, respectively. This model displayed a concordance index (C-index) of 0.834 and was validated in both the internal (C-index, 0.830) and external (C-index, 0.817) sets. The incidence of CISLD was significantly reduced in those who received preventive hepatoprotective drugs compared to those who did not among patients assessed as the intermediate risk group (8.9% vs 17.5%, p=0.042) and the high risk group (15.6% vs 55.8%, p=0.043). Conclusions The new score model can be used to accurately predict the risk of CISLD in cancer patients undergoing chemotherapy. Clinically, this can be translated into a reference tool for oncologists in the clinical decision-making process before chemotherapy to provide appropriate prevention and interventions for patients with a high risk of CISLD.
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Affiliation(s)
- Mengping Zhang
- Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yong Bao
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Chen
- Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mengchao Wei
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Pang
- Department of Medical Records Management, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu Feng Ren
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jie Mei
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sheng Ye
- Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shunjun Fu
- Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhen Wei Peng
- Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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23
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Dacosta-Noble P, Costantini A, Dumenil C, Dumoulin J, Helly de Tauriers P, Giraud V, Labrune S, Emile JF, Alvarez JC, Chinet T, Giroux Leprieur E. Positive plasma cotinine during platinum-based chemotherapy is associated with poor response rate in advanced non-small cell lung cancer patients. PLoS One 2019; 14:e0219080. [PMID: 31260495 PMCID: PMC6602197 DOI: 10.1371/journal.pone.0219080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 06/14/2019] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Patients with advanced non-small cell lung cancer (NSCLC) are most of the time treated with a first-line cytotoxic chemotherapy. Tobacco use is responsible for 90% of lung cancer. The aim of this study was to evaluate the impact of smoking continuation during first-line chemotherapy on tumor response in advanced-stage NSCLC. MATERIALS AND METHODS All patients with an advanced-stage NSCLC (IIIb or IV), treated with first-line platinum-based chemotherapy in our Department between June 2013 and July 2017 were included. Smoking status was assessed at inclusion by self-report, then at the tumor assessment consultation after 2 months of treatment, by both self-report and plasmatic cotinine measurement. Chemotherapy response, progression-free survival (PFS), overall survival (OS) and stage 3-4 toxicity were registered. RESULTS Ninety-seven patients were included: 8 (8%) declared to be non-smokers, 56 (58%) current smokers and 33 (34%) former smokers at diagnosis. At the first tumor evaluation, 24 (25%) self-reported as active smokers and 73 (75%) as non-smokers; overall response rate (ORR) was respectively 38% and 48% (p = 0.373). Fifty-four patients had a plasmatic cotinine evaluation at the first tumor evaluation. Seventeen patients (32%) had a positive cotinine rate (median 108ng/mL, IQR 31-236). Six patients (35%) had positive cotinine rate whereas declaring to be non-smokers at the first tumor evaluation. ORR was 18% in case of positive cotinine rate, and 57% when negative (p = 0.007). Regardless of the method for smoking status evaluation, PFS, OS and grade 3-4 toxicities were similar between smoker and non-smoker patients at the first tumor evaluation. CONCLUSION Smoking continuation during platinum-based chemotherapy, reflected by positive plasma cotinine rate, was associated with a poor ORR.
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Affiliation(s)
- Philippine Dacosta-Noble
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
| | - Adrien Costantini
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
- EA 4340, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France
| | - Coraline Dumenil
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
- EA 4340, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France
| | - Jennifer Dumoulin
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
| | - Pierre Helly de Tauriers
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
| | - Violaine Giraud
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
| | - Sylvie Labrune
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
| | - Jean-François Emile
- EA 4340, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France
- Centre de Ressources Biologiques, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
| | - Jean-Claude Alvarez
- AP-HP, Hôpital Raymond Poincaré, Service de Pharmacologie Toxicologie, INSERM U-1173, UVSQ, Université Paris-Saclay, Garches, France
| | - Thierry Chinet
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
- EA 4340, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France
| | - Etienne Giroux Leprieur
- Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France
- EA 4340, UVSQ, Université Paris-Saclay, Boulogne-Billancourt, France
- * E-mail:
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24
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Yamada Y, Fujii H, Ohata K, Kato-Hayashi H, Watanabe D, Ishihara T, Uemura S, Iwashita T, Imai H, Matsuhashi N, Takahashi T, Sugiyama T, Shimizu M, Yoshida K, Suzuki A. High total bilirubin level is a significant risk factor for severe neutropenia in patients receiving irinotecan-based chemotherapy. Med Oncol 2019; 36:63. [DOI: 10.1007/s12032-019-1288-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 05/28/2019] [Indexed: 01/28/2023]
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25
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Abstract
Tobacco smoking accounts for at least 30% of all cancer deaths and nearly 90% of lung cancer deaths. Smoking cessation significantly reduces the risk of developing tobacco-related malignancies. Smoking after cancer diagnosis is also associated with multiple risks, including worse tolerance of treatment, higher risk of a failure and second primary tumors, and poorer quality of life. Apart from disease site and stage, continued smoking is considered the strongest adverse predictor of survival in cancer patients. However, the benefits of smoking cessation are undervalued: many patients are not aware of harms related to continued tobacco use after cancer diagnosis. Furthermore, health care professionals often do not encourage their patients to quit, and do not provide tobacco cessation assistance for continuing tobacco users. Despite the apparent impact of tobacco use on treatment outcomes, data on current smoking status is only rarely captured in clinical trials This article reviews the most important clinical aspects of smoking after the diagnosis of cancer.
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Affiliation(s)
- Jacek Jassem
- Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland
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26
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Giuliani ME, Liu G, Xu W, Dirlea M, Selby P, Papadakos J, Abdelmutti N, Yang D, Eng L, Goldstein DP, Jones JM. Implementation of a Novel Electronic Patient-Directed Smoking Cessation Platform for Cancer Patients: Interrupted Time Series Analysis. J Med Internet Res 2019; 21:e11735. [PMID: 30964445 PMCID: PMC6477574 DOI: 10.2196/11735] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 12/20/2018] [Accepted: 12/31/2018] [Indexed: 01/16/2023] Open
Abstract
Background Continued smoking in cancer patients undergoing treatment results in significantly higher rates of treatment toxicities and persistent effects, increased risk of recurrence and second malignancy, and increased all-cause mortality. Despite this, routine tobacco use screening and the provision of smoking cessation treatment has yet to be implemented widely in the cancer setting. Objective The objective of this study was to implement and evaluate the adoption and impact of an innovative Smoking Cessation e-referral System (CEASE) to promote referrals to smoking cessation programs in cancer patients. Methods A patient-directed electronic smoking cessation platform (CEASE) was developed to promote smoking screening and referral and implemented at 1 of Canada’s largest cancer centers. The implementation and evaluation were guided by the Ottawa Model of Research Use. An interrupted time series design was used to examine the impact of CEASE on screening rates, referrals offered, and referrals accepted compared with a previous paper-based screening program. A subsample of smokers or recent quitters was also assessed and compared pre- and postimplementation to examine the effect of CEASE on subsequent contact with smoking cessation programs and quit attempts. Results A total of 17,842 new patients attended clinics over the 20-month study period. The CEASE platform was successfully implemented across all disease sites. Screening rates increased from 44.28% (2366/5343) using the paper-based approach to 65.72% (3538/5383) using CEASE (P<.01), and referrals offered to smokers who indicated interest in quitting increased from 18.6% (58/311) to 98.8% (421/426; P<.01). Accepted referrals decreased from 41% (24/58) to 20.4% (86/421), though the overall proportion of referrals generated from total current/recent tobacco users willing to quit increased from 5.8% (24/414) to 20.2% (86/426) due to the increase in referrals offered. At 1-month postscreening, there was no significant difference in the proportion that was currently using tobacco and had not changed use in the past 4 weeks (pre: 28.9% [24/83] and post: 28.8% [83/288]). However, contact with the referral program increased from 0% to 78% in the postCEASE cohort (P<.001). Conclusions CEASE is an innovative tool to improve smoking screening and can be implemented in both a time- and cost-effective manner which promotes sustainability. CEASE was successfully implemented across all clinics and resulted in improvements in overall screening and referral rates and engagement with referral services.
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Affiliation(s)
| | - Geoffrey Liu
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Wei Xu
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | | | - Peter Selby
- Centre for Addiction and Mental Health, Toronto, ON, Canada
| | | | | | - Dongyang Yang
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Lawson Eng
- Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada
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27
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Tang F, Tsakalozou E, Arnold SM, Ng CM, Leggas M. Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue, in cancer patients with solid tumors. Invest New Drugs 2019; 37:1218-1230. [PMID: 30820810 DOI: 10.1007/s10637-019-00744-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/06/2019] [Indexed: 01/11/2023]
Abstract
Background AR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent. Methods Pharmacokinetic data collected in the phase 1 clinical trial were utilized for the development of a population POP PK by implementing the non-linear mixed effects approach. Patient characteristics at study entry were evaluated as covariates in the model. Subjects (N = 26) were treated at nine dosage levels (1.2-12.4 mg/m2/day) on a daily × 5 schedule. Hematological toxicity data were modeled against exposure metrics. Results A two-compartment POP PK model best described the disposition of AR-67 by fitting a total of 328 PK observations from 25 subjects. Following covariate model selection, age remained as a significant covariate on central volume. The final model provided a good fit for the concentration versus time data and PK parameters were estimated with good precision. Clearance, inter-compartmental clearance, central volume and peripheral volume were estimated to be 32.2 L/h, 28.6 L/h, 6.83 L and 25.0 L, respectively. Finally, exposure-pharmacodynamic analysis using Emax models showed that plasma drug concentration versus time profiles are better predictors of AR-67-related hematologic toxicity were better predictors of leukopenia and thrombocytopenia, as compared to total dose. Conclusions A POP PK model was developed to characterize AR-67 pharmacokinetics and identified age as a significant covariate. Exposure PK metrics Cmax and AUC were shown to predict hematological toxicity. Further efforts to identify clinically relevant determinants of AR-67 disposition and effects in a larger patient population are warranted.
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Affiliation(s)
- Fei Tang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536, USA
| | - Eleftheria Tsakalozou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536, USA
| | - Susanne M Arnold
- Department of Internal Medicine, Division of Medical Oncology, Markey Cancer Center, University of Kentucky, 800 Rose St., Lexington, KY 40536, Lexington, KY, 40536, USA.,National Cancer Institute Designated Markey Cancer Center, Lexington Kentucky, Lexington, KY, USA
| | - Chee M Ng
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536, USA.,National Cancer Institute Designated Markey Cancer Center, Lexington Kentucky, Lexington, KY, USA
| | - Markos Leggas
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone St., Lexington, KY, 40536, USA. .,National Cancer Institute Designated Markey Cancer Center, Lexington Kentucky, Lexington, KY, USA.
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28
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Fragoulis GE, Paterson C, Gilmour A, Derakhshan MH, McInnes IB, Porter D, Siebert S. Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome. RMD Open 2018; 4:e000739. [PMID: 30402267 PMCID: PMC6203094 DOI: 10.1136/rmdopen-2018-000739] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/06/2018] [Accepted: 08/16/2018] [Indexed: 12/30/2022] Open
Abstract
Objectives To determine the frequency, severity and natural history of neutropaenia in early rheumatoid arthritis (RA), explore its associations with clinical features and assess its impact on clinical management. Methods The Scottish Early Rheumatoid Arthritis inception cohort prospectively recruited patients with newly diagnosed RA and followed them up every 6 months. Patients with RA who developed at least one episode of neutropaenia (grade 1: <2.0×10^9/L; grade 2: <1.5×10^9/L; grade 3: <1.0×10^9/L; grade 4: <0.5×10^9/L) were compared with those who did not. Comparisons were also made between patients who experienced one or more episodes of neutropaenia and between patients with different neutropaenia grades. Results 77 neutropaenia episodes were recorded in 58 of 771 (7.5%) patients with RA, who were followed up for a median (range) of 18 (6-48) months. Neutropaenia occurred at a median (range) of 12 (0-120) months after RA diagnosis. The majority had mild neutropaenia (grade 1: n=42; grade 2: n=14; grade 3: n=1; grade 4: n=1). Neutropaenia was transient (single episode) in the majority (44; 75.8%) of cases but led to treatment discontinuation in 14 (24.1%) patients. Patients who developed neutropaenia were more likely to be female (p=0.01) and non-smokers (p=0.007) and had lower baseline neutrophil levels (p<0.0001). Binomial regression analysis confirmed the latter (p<0.0001, B: -0.491) as neutropaenia predictor. The rate of infections did not differ between patients who developed neutropaenia and those who did not (p=0.878). Conclusion Neutropaenia was a common finding in this cohort. It was usually mild, transient and not associated with increased infection rates. Neutropaenia occurrence was associated with non-smoking, female gender and lower baseline neutrophil levels.
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Affiliation(s)
- George E Fragoulis
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Caron Paterson
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Ashley Gilmour
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Mohammad H Derakhshan
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Duncan Porter
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Stefan Siebert
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
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29
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CYP1A1 and 1B1-mediated metabolic pathways of dolutegravir, an HIV integrase inhibitor. Biochem Pharmacol 2018; 158:174-184. [PMID: 30342022 DOI: 10.1016/j.bcp.2018.10.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 10/15/2018] [Indexed: 11/23/2022]
Abstract
Dolutegravir (DTG), a potent integrase inhibitor, is part of a recommended initial regimen for the treatment of human immunodeficiency virus (HIV). Prior reports demonstrated that the clearance of DTG was higher in current smokers than non-smokers, but the mechanism remains unclear. Using a metabolomic approach, M4 (an aldehyde) was identified as a novel metabolite of DTG. In addition, the formation of M4 was found to be mediated by cytochrome P450 (CYP) 1A1 and 1B1, the enzymes that can be highly induced by cigarette smoking. CYP1A1 and 1B1 were also identified as the major enzymes contributing to the formation of M1 (an N-dealkylated metabolite of DTG) and M5 (an aldehyde). Furthermore, the production of M1 and M4 was significantly increased in the lung of mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin, an inducer of CYP1A1 and 1B1. In summary, the current study uncovered the CYP1A1 and 1B1-mediated metabolic pathways of DTG. These data suggest that persons with HIV infection receiving DTG should be cautious to cigarettes, and drugs, or exposure to environmental chemicals that induce CYP1A1 and 1B1.
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30
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Tsuboya A, Fujita KI, Kubota Y, Ishida H, Taki-Takemoto I, Kamei D, Iwai S, Sasaki Y. Coadministration of cytotoxic chemotherapeutic agents with irinotecan is a risk factor for irinotecan-induced cholinergic syndrome in Japanese patients with cancer. Int J Clin Oncol 2018; 24:222-230. [DOI: 10.1007/s10147-018-1347-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 09/16/2018] [Indexed: 12/01/2022]
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31
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Effects of smoking and body mass index on the exposure of fentanyl in patients with cancer. PLoS One 2018; 13:e0198289. [PMID: 29883454 PMCID: PMC5993275 DOI: 10.1371/journal.pone.0198289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/15/2018] [Indexed: 11/19/2022] Open
Abstract
The transdermal fentanyl patch is widely used to treat cancer-related pain despite its wide inter- and intrapatient variability in pharmacokinetics. The aim of this study was to investigate whether smoking and body size (i.e. body mass index) influence fentanyl exposure in patients with cancer. These are factors that typically change during treatment and disease trajectories. We performed an explorative cohort study in patients with cancer using transdermal fentanyl patches (Durogesic®), by taking a blood sample for pharmacokinetic analysis one day after applying a patch in patients with a stable fentanyl dose. A total of 88 patients were evaluable. Although no statistically significant difference was found, the plasma concentrations of non-smokers was 28% (95% CI [-14%; +89-%]) higher than those of smokers normalizing for a dose of 25μg/min. Patients with a low BMI (< 20 kg/m2) had almost similar (10% (95% CI [-39%; +97%]) higher) plasma concentrations compared to patients with a high BMI (> 25 kg/m2). A wider variation in fentanyl plasma concentrations was found in this study than anticipated. Due to this variation, studies in larger patient cohorts are needed to further investigate the effect of smoking on plasma concentration of fentanyl and thereby clarify the clinical significance of our findings.
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32
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Lim C, Cohn JR, Cohn JA. Can a diagnosis of bladder cancer motivate positive lifestyle changes-and prevent recurrent disease? Transl Androl Urol 2018; 7:S242-S245. [PMID: 29928624 PMCID: PMC5989117 DOI: 10.21037/tau.2018.04.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Affiliation(s)
- Caitlin Lim
- Department of Urology, Einstein Healthcare Network, Philadelphia, PA, USA
| | - John R Cohn
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, USA
| | - Joshua A Cohn
- Department of Urology, Einstein Healthcare Network, Philadelphia, PA, USA.,Department of Surgical Oncology, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
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33
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Korean Society of Thyroid-Head and Neck Surgery Guideline Task Force, Ahn SH, Hong HJ, Kwon SY, Kwon KH, Roh JL, Ryu J, Park JH, Baek SK, Lee GH, Lee SY, Lee JC, Chung MK, Joo YH, Ji YB, Hah JH, Kwon M, Park YM, Song CM, Shin SC, Ryu CH, Lee DY, Lee YC, Chang JW, Jeong HM, Cho JK, Cha W, Chun BJ, Choi IJ, Choi HG, Lee KD. Guidelines for the Surgical Management of Laryngeal Cancer: Korean Society of Thyroid-Head and Neck Surgery. Clin Exp Otorhinolaryngol 2017; 10:1-43. [PMID: 28043099 PMCID: PMC5327593 DOI: 10.21053/ceo.2016.01389] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 10/24/2016] [Indexed: 01/08/2023] Open
Abstract
Korean Society of Thyroid-Head and Neck Surgery appointed a Task Force to develop clinical practice guidelines for the surgical treatment of laryngeal cancer. This Task Force conducted a systematic search of the EMBASE, MEDLINE, Cochrane Library, and KoreaMed databases to identify relevant articles, using search terms selected according to the key questions. Evidence-based recommendations were then created on the basis of these articles. An external expert review and Delphi questionnaire were applied to reach consensus regarding the recommendations. The resulting guidelines focus on the surgical treatment of laryngeal cancer with the assumption that surgery is the selected treatment modality after a multidisciplinary discussion in any context. These guidelines do not, therefore, address non-surgical treatment such as radiation therapy or chemotherapy. The committee developed 62 evidence-based recommendations in 32 categories intended to assist clinicians during management of patients with laryngeal cancer and patients with laryngeal cancer, and counselors and health policy-makers.
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Affiliation(s)
- Korean Society of Thyroid-Head and Neck Surgery Guideline Task Force
- Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Catholic Kwandong University College of Medicine, Incheon, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Hallym University College of Medicine, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, University of Ulsan College of Medicine, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, National Cancer Center, Goyang, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Chosun University College of Medicine, Gwangju, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Korea Cancer Center Hospital, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine, Busan, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Hanyang University College of Medicine, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Gyeongsang National University School of Medicine, Jinju, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Daejin Medical Center, Bundang Jesaeng Hospital, Seongnam, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Kyung Hee University School of Medicine, Seoul, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Chungnam National University School of Medicine, Daejeon, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Wonkwang University School of Medicine, Iksan, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Inje University College of Medicine, Busan, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Seonam University College of Medicine, Goyang, Korea
- Department of Otorhinolaryngology Head and Neck Surgery, Kosin University College of Medicine, Busan, Korea
| | - Soon-Hyun Ahn
- Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Jun Hong
- Department of Otorhinolaryngology Head and Neck Surgery, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Soon Young Kwon
- Department of Otorhinolaryngology Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea
| | - Kee Hwan Kwon
- Department of Otorhinolaryngology Head and Neck Surgery, Hallym University College of Medicine, Seoul, Korea
| | - Jong-Lyel Roh
- Department of Otorhinolaryngology Head and Neck Surgery, University of Ulsan College of Medicine, Seoul, Korea
| | - Junsun Ryu
- Department of Otorhinolaryngology Head and Neck Surgery, National Cancer Center, Goyang, Korea
| | - Jun Hee Park
- Department of Otorhinolaryngology Head and Neck Surgery, Chosun University College of Medicine, Gwangju, Korea
| | - Seung-Kuk Baek
- Department of Otorhinolaryngology Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea
| | - Guk Haeng Lee
- Department of Otorhinolaryngology Head and Neck Surgery, Korea Cancer Center Hospital, Seoul, Korea
| | - Sei Young Lee
- Department of Otorhinolaryngology Head and Neck Surgery, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jin Choon Lee
- Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine, Busan, Korea
| | - Man Ki Chung
- Department of Otorhinolaryngology Head and Neck Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Hoon Joo
- Department of Otorhinolaryngology Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yong Bae Ji
- Department of Otorhinolaryngology Head and Neck Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Jeong Hun Hah
- Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Minsu Kwon
- Department of Otorhinolaryngology Head and Neck Surgery, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Young Min Park
- Department of Otorhinolaryngology Head and Neck Surgery, Daejin Medical Center, Bundang Jesaeng Hospital, Seongnam, Korea
| | - Chang Myeon Song
- Department of Otorhinolaryngology Head and Neck Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Sung-Chan Shin
- Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine, Busan, Korea
| | - Chang Hwan Ryu
- Department of Otorhinolaryngology Head and Neck Surgery, National Cancer Center, Goyang, Korea
| | - Doh Young Lee
- Department of Otorhinolaryngology Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea
| | - Young Chan Lee
- Department of Otorhinolaryngology Head and Neck Surgery, Kyung Hee University School of Medicine, Seoul, Korea
| | - Jae Won Chang
- Department of Otorhinolaryngology Head and Neck Surgery, Chungnam National University School of Medicine, Daejeon, Korea
| | - Ha Min Jeong
- Department of Otorhinolaryngology Head and Neck Surgery, Wonkwang University School of Medicine, Iksan, Korea
| | - Jae-Keun Cho
- Department of Otorhinolaryngology Head and Neck Surgery, Inje University College of Medicine, Busan, Korea
| | - Wonjae Cha
- Department of Otorhinolaryngology Head and Neck Surgery, Pusan National University School of Medicine, Busan, Korea
| | - Byung Joon Chun
- Department of Otorhinolaryngology Head and Neck Surgery, Seonam University College of Medicine, Goyang, Korea
| | - Ik Joon Choi
- Department of Otorhinolaryngology Head and Neck Surgery, Korea Cancer Center Hospital, Seoul, Korea
| | - Hyo Geun Choi
- Department of Otorhinolaryngology Head and Neck Surgery, Hallym University College of Medicine, Seoul, Korea
| | - Kang Dae Lee
- Department of Otorhinolaryngology Head and Neck Surgery, Kosin University College of Medicine, Busan, Korea
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Neradugomma NK, Liao MZ, Mao Q. Buprenorphine, Norbuprenorphine, R-Methadone, and S-Methadone Upregulate BCRP/ABCG2 Expression by Activating Aryl Hydrocarbon Receptor in Human Placental Trophoblasts. Mol Pharmacol 2017; 91:237-249. [PMID: 27974484 PMCID: PMC5325079 DOI: 10.1124/mol.116.107367] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 12/13/2016] [Indexed: 12/24/2022] Open
Abstract
Opioid dependence during pregnancy is a rising concern. Maintaining addicted pregnant women on long-acting opioid receptor agonist is the most common strategy to manage drug abuse in pregnant women. Methadone (MET) and buprenorphine (BUP) are widely prescribed for opiate maintenance therapy. Norbuprenorphine (NBUP) is the primary active metabolite of BUP. These medications can cross the placenta to the fetus, leading to postpartum neonatal abstinence syndrome. Despite their use during pregnancy, little is known about the cellular changes in the placenta brought about by these drugs. In this study, we showed that BUP, NBUP, and MET at clinically relevant plasma concentrations significantly induced BCRP mRNA up to 10-fold in human model placental JEG3 and BeWo cells and in primary human villous trophoblasts, and this induction was abrogated by CH223191, an aryl hydrocarbon receptor (AhR)-specific antagonist. These drugs increased AhR recruitment onto the AhR-response elements and significantly induced breast cancer resistance protein (BCRP) gene transcription. AhR overexpression further increased BCRP mRNA and protein expression. Knockdown of AhR by shRNA decreased BCRP expression, and this decrease was reversed by rescuing AhR expression. Finally, induction of BCRP expression in JEG3 and BeWo cells was accompanied by an increase in its efflux activity. Collectively, we have demonstrated, for the first time, that BUP, NBUP, and MET are potent AhR agonists and can induce BCRP in human placental trophoblasts by activating AhR. Given the critical role of BCRP in limiting fetal exposure to drugs and xenobiotics, long-term use of these medications may affect fetal drug exposure by altering BCRP expression in human placenta.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism
- Buprenorphine/analogs & derivatives
- Buprenorphine/pharmacology
- Female
- Gene Knockdown Techniques
- Humans
- Ligands
- Methadone/pharmacology
- Placenta/cytology
- Pregnancy
- Promoter Regions, Genetic/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Aryl Hydrocarbon/antagonists & inhibitors
- Receptors, Aryl Hydrocarbon/metabolism
- Transcription, Genetic/drug effects
- Trophoblasts/drug effects
- Trophoblasts/metabolism
- Up-Regulation/drug effects
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Affiliation(s)
- Naveen K Neradugomma
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
| | - Michael Z Liao
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
| | - Qingcheng Mao
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Chang EHE, Braith A, Hitsman B, Schnoll RA. Treating Nicotine Dependence and Preventing Smoking Relapse in Cancer Patients. EXPERT REVIEW OF QUALITY OF LIFE IN CANCER CARE 2016; 2:23-39. [PMID: 28808692 PMCID: PMC5553981 DOI: 10.1080/23809000.2017.1271981] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Despite the well-documented harmful effects of smoking, many cancer patients continue to smoke. Smoking cessation is critical to address in this population given the associated increase in treatment toxicity, risk of second primary tumors, decrease in treatment response and higher disease-specific and all-cause mortality with continued smoking following a cancer diagnosis. This review seeks to summarize the latest recommendations and guidelines on smoking cessation treatment for patients diagnosed with cancer, and the evidence behind those recommendations. AREAS COVERED We reviewed the latest evidence for smoking cessation treatments for cancer patients and the clinical guidelines and recommendation available for oncologists and health care providers. The unique aspects of nicotine dependence among patients diagnosed with cancer, and key challenges and barriers that cancer survivors and health care providers experience when considering smoking cessation treatments, and available clinical resources, are also discussed. Lastly, the authors summarize future directions in the field of smoking cessation treatment for cancer patients. EXPERT COMMENTARY While there are areas of improvement in research of smoking cessation treatment for cancer patients, critical under-explored areas remain. Nonetheless, providers should adhere to the NCCN guidelines and offer a brief counseling intervention to motivate patients to quit smoking when appropriate resources are not available.
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Affiliation(s)
- Eun Hae Estelle Chang
- Department of Otolaryngology Head and Neck Surgery, University of Nebraska Medical Center, 981225 Nebraska Medical Center, Omaha, NE 68198-1225, Phone 402-559-8007 Fax 402-559-8490
| | - Andrew Braith
- College of Medicine, University of Nebraska Medical Center, 42 Street and Emile Street, Omaha, NE 68198
| | - Brian Hitsman
- Department of Preventive Medicine, Feinberg School of Medicine & Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 680 N Lake Shore Drive, Suite 1400, Chicago, IL 60611, Phone 312-503-2074
| | - Robert A Schnoll
- Department of Psychiatry and Abramson Cancer Center, University of Pennsylvania, 3535 Market Street, 4 Floor, Philadelphia, PA 19104, Phone 215-746-7143 Fax 215-746-7140
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Rivera C, Rivera S, Fabre E, Pricopi C, Le Pimpec-Barthes F, Riquet M. [Consequences of tobacco smoking on lung cancer treatments]. REVUE DE PNEUMOLOGIE CLINIQUE 2016; 72:136-141. [PMID: 25727658 DOI: 10.1016/j.pneumo.2014.11.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 11/10/2014] [Accepted: 11/18/2014] [Indexed: 06/04/2023]
Abstract
In France, in 2010, tobacco induced 81% of deaths by lung cancer corresponding to about 28,000 deaths. Continued smoking after diagnosis has a significant impact on treatment. In patients with lung cancer, the benefits of smoking cessation are present at any stage of disease. For early stages, smoking cessation decreases postoperative morbidity, reduces the risk of second cancer and improves survival. Previous to surgery, smoking cessation of at least six to eight weeks or as soon as possible is recommended in order to reduce the risk of infectious complications. Tobacco could alter the metabolism of certain chemotherapies and targeted therapies, such as tyrosine kinase inhibitors of the EGF receptor, through an interaction with P450 cytochrome. Toxicity of radiations could be lower in patients with lung cancer who did not quit smoking before treatment. For patients treated by radio-chemotherapy, overall survival seems to be better in former smokers but no difference is observed in terms of recurrence-free survival. For advanced stages, smoking cessation enhances patients' quality of life. Smoking cessation should be considered as full part of lung cancer treatment whatever the stage of disease.
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Affiliation(s)
- C Rivera
- Service de chirurgie thoracique et transplantation pulmonaire, université Paris Descartes, hôpital européen Georges-Pompidou, 20-40, rue Leblanc, 75015 Paris, France
| | - S Rivera
- Service de radiothérapie, institut Gustave-Roussy, 94800 Villejuif, France
| | - E Fabre
- Service d'oncologie médicale, université Paris-Descartes, hôpital européen Georges-Pompidou, 75015 Paris, France
| | - C Pricopi
- Service de chirurgie thoracique et transplantation pulmonaire, université Paris Descartes, hôpital européen Georges-Pompidou, 20-40, rue Leblanc, 75015 Paris, France
| | - F Le Pimpec-Barthes
- Service de chirurgie thoracique et transplantation pulmonaire, université Paris Descartes, hôpital européen Georges-Pompidou, 20-40, rue Leblanc, 75015 Paris, France
| | - M Riquet
- Service de chirurgie thoracique et transplantation pulmonaire, université Paris Descartes, hôpital européen Georges-Pompidou, 20-40, rue Leblanc, 75015 Paris, France.
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Fujita KI, Kubota Y, Ishida H, Sasaki Y. Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer. World J Gastroenterol 2015; 21:12234-12248. [PMID: 26604633 PMCID: PMC4649109 DOI: 10.3748/wjg.v21.i43.12234] [Citation(s) in RCA: 220] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 09/05/2015] [Accepted: 10/26/2015] [Indexed: 02/06/2023] Open
Abstract
Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy.
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Abstract
OBJECTIVE Smoking may affect pharmacokinetics of chemotherapeutic agents and hemodynamics of the smokers, thereby influencing adverse events and efficacy of chemotherapy in patients with pancreatic cancer (PC). The aim of this study was to clarify how smoking totally affected patients with PC receiving current chemotherapy. METHODS We evaluated the impact of smoking status on the performance of chemotherapy and survival in 262 patients with PC including 158 resectable and 104 unresectable PC. RESULTS There were more male and younger patients in current smokers than in nonsmokers. In unresectable PC, current smokers had more metastatic tumors than locally advanced tumors compared with nonsmokers. In current smokers receiving chemotherapy, the baseline white blood cell count, neutrophil count, and hemoglobin concentration were significantly higher in current smokers than in nonsmokers. Furthermore, grades 3 to 4 neutropenia was observed more often in nonsmokers than smokers. On the other hand, the performance and efficacy of the planned adjuvant chemotherapy were similar between smokers and nonsmokers. More importantly, there was no significant difference in overall prognosis between smokers and nonsmokers receiving chemotherapy. CONCLUSIONS Smoking status has no significant impact on the efficacy of current chemotherapy for both resectable and unresectable PC.
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Urban T, Underner M, Hureaux J, Quantin X. Tobacco control. Lung Cancer 2015. [DOI: 10.1183/2312508x.10009514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Zhang J, Hayes S, Sadler BM, Minto I, Brandt J, Piscitelli S, Min S, Song IH. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients. Br J Clin Pharmacol 2015; 80:502-14. [PMID: 25819132 PMCID: PMC4574835 DOI: 10.1111/bcp.12639] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 02/19/2015] [Accepted: 03/22/2015] [Indexed: 11/28/2022] Open
Abstract
Aim Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates. Methods A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10–50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine. Results The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h–1, 17.4 l, 2.24 h−1, and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co-infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis. Conclusions A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients.
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Affiliation(s)
- Jianping Zhang
- Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC, USA
| | | | | | - Ilisse Minto
- GlaxoSmithKline, Research Triangle Park, NC, USA
| | - Julie Brandt
- GlaxoSmithKline, Research Triangle Park, NC, USA
| | - Steve Piscitelli
- Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC, USA
| | - Sherene Min
- GlaxoSmithKline, Research Triangle Park, NC, USA
| | - Ivy H Song
- Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC, USA
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Jiménez-Ruiz CA, Andreas S, Lewis KE, Tonnesen P, van Schayck CP, Hajek P, Tonstad S, Dautzenberg B, Fletcher M, Masefield S, Powell P, Hering T, Nardini S, Tonia T, Gratziou C. Statement on smoking cessation in COPD and other pulmonary diseases and in smokers with comorbidities who find it difficult to quit. Eur Respir J 2015; 46:61-79. [PMID: 25882805 DOI: 10.1183/09031936.00092614] [Citation(s) in RCA: 125] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 12/24/2014] [Indexed: 12/18/2022]
Abstract
Chronic obstructive pulmonary disease (COPD), lung cancer, asthma and pulmonary tuberculosis are common pulmonary diseases that are caused or worsened by tobacco smoking. Growing observational evidence suggests that symptoms and prognosis of these conditions improve upon smoking cessation. Despite increasing numbers of (small) randomised controlled trials suggesting intensive smoking cessation treatments work in people with pulmonary diseases many patients are not given specific advice on the benefits or referred for intensive cessation treatments and, therefore, continue smoking.This is a qualitative review regarding smoking cessation in patients with COPD and other pulmonary disorders, written by a group of European Respiratory Society experts. We describe the epidemiological links between smoking and pulmonary disorders, the evidence for benefits of stopping smoking, how best to assess tobacco dependence and what interventions currently work best to help pulmonary patients quit. Finally, we describe characteristics and management of any "hardcore" smoker who finds it difficult to quit with standard approaches.
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Affiliation(s)
| | - Stefan Andreas
- Lungenfachklinik Immenhausen and Pneumology, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Keir E Lewis
- Dept of Respiratory Medicine, Prince Philip Hospital and Swansea College of Medicine, Swansea, UK
| | - Philip Tonnesen
- Dept of Sleep Medicine, Glostrup Hospital, Glostrup, Denmark
| | - C P van Schayck
- Care and Public Health Research Institute (Caphri), Maastricht University, Maastricht, The Netherlands
| | - Peter Hajek
- Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
| | - Serena Tonstad
- Section for Preventive Cardiology, Oslo University Hospital, Oslo, Norway
| | | | | | | | | | | | - Stefano Nardini
- Pulmonary and TB Unit, Ospedale Civile, Vittorio Veneto, Italy
| | - Thomy Tonia
- Institute of Social and Preventive Medicine, University of Bern, Switzerland
| | - Christina Gratziou
- University Centre for Research and Smoking Cessation, Evgenidio Hospital, Medical School, Athens University, Athens, Greece
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O'Malley SS, Gueorguieva R, Wu R, Jatlow PI. Acute alcohol consumption elevates serum bilirubin: an endogenous antioxidant. Drug Alcohol Depend 2015; 149:87-92. [PMID: 25707709 PMCID: PMC4540054 DOI: 10.1016/j.drugalcdep.2015.01.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 01/19/2015] [Accepted: 01/20/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND Moderate alcohol consumption has been associated with both negative and favorable effects on health. The mechanisms responsible for reported favorable effects remain unclear. Higher (not necessarily elevated) concentrations of serum bilirubin, an antioxidant, have also been associated with reduced risk of cardiovascular disease and all-cause mortality. This study tests the hypothesis that single dose alcohol consumption elevates bilirubin providing a potential link between these observations. METHODS 18 healthy individuals (eight cigarette smokers) were administered alcohol, calibrated to achieve blood concentrations of 20, 80 and 120 mg/dL, in random order in three laboratory sessions separated by a week. Each session was preceded by and followed by 5-7 days of alcohol abstinence. Serum bilirubin was measured at 7:45 a.m. prior to drinking, at 2p.m., and at 7:45 the next morning. Mixed effects regression models compared baseline and 24h post-drinking bilirubin concentrations. RESULTS Total serum bilirubin (sum of indirect and direct) concentration increased significantly after drinking from baseline to 24h in non-smokers (from M = 0.38, SD = 0.24 to M = 0.51, SD = 0.30, F(1,32.2) = 24.24, p<.0001) but not in smokers (from M = 0.25, SD = 0.12 to M = 0.26, SD = 0.15, F(1,31.1) = 0.04, p = 0.84). In nonsmokers the indirect bilirubin concentration and the ratio of indirect (unconjugated) to direct (conjugated) bilirubin also increased significantly. CONCLUSIONS Alcohol consumption leads to increases in serum bilirubin in nonsmokers. Considering the antioxidant properties of bilirubin, our findings suggest one possible mechanism for the reported association between alcohol consumption and reduced risk of some disorders that could be tested in future longitudinal studies.
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Affiliation(s)
- Stephanie S O'Malley
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States; Yale Cancer Center, Yale School of Medicine, New Haven, CT, United States.
| | - Ralitza Gueorguieva
- Department of Biostatistics, Yale Schools of Public Health and Medicine, New Haven, CT, United States.
| | - Ran Wu
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States.
| | - Peter I Jatlow
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, United States; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, United States.
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Chandar M, de Wilton Marsh R. Severe Generalized Weakness, Paralysis, and Aphasia following Administration of Irinotecan and Oxaliplatin during FOLFIRINOX Chemotherapy. Case Rep Oncol 2015; 8:138-41. [PMID: 25873880 PMCID: PMC4376921 DOI: 10.1159/000380849] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Irinotecan is commonly used in combination with oxaliplatin as a component of FOLFIRINOX chemotherapy for several gastrointestinal malignancies. The purpose of this case report is to describe a patient who developed acute paralysis and aphasia while receiving her initial infusion of irinotecan. CASE REPORT A 67-year-old woman with newly diagnosed metastatic pancreatic adenocarcinoma presented for her first cycle of FOLFIRINOX chemotherapy. During her infusion of irinotecan, she developed acute onset of generalized weakness, paralysis of all extremities, and nonfluent aphasia with complete inability to communicate. This episode was self-limited and resolved within 2 h. Prior to subsequent infusions she received intravenous repletion of potassium and had no recurrence of symptoms. DISCUSSION In selected cases, coadministration of irinotecan and oxaliplatin may result in severe generalized weakness and aphasia, which may be triggered by underlying electrolyte disturbances. Careful monitoring and correction of potassium may help prevent this reaction.
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Affiliation(s)
- Manisha Chandar
- University of Chicago (North Shore), North Shore University Health System, Evanston, Ill., USA
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Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer. J Thorac Oncol 2015; 9:917-926. [PMID: 24926542 DOI: 10.1097/jto.0000000000000191] [Citation(s) in RCA: 84] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Cigarette smoke associated polycyclic aromatic hydrocarbons can induce key drug-metabolizing enzymes of cytochrome P450 and isoforms of the glucuronyl transferases families. These enzymes metabolize several systemic therapies for lung cancer. Induction of these enzymes may lead to accelerated clearance with resultant impact on systemic therapy efficacy and toxicity in smokers compared with nonsmokers. This article reviews published literature regarding the influence of smoking as it relates to alteration of metabolism of systemic therapy in lung cancer. METHODS A structured search of the National Library of Medicine's PubMed/MEDLINE identified relevant articles. Data were abstracted and analyzed to summarize the findings. RESULTS Studies that analyzed pharmacokinetic data were prospective. Smokers receiving erlotinib exhibited rapid clearance, requiring a higher dose to reach equivalent systemic exposure compared with nonsmokers. Smokers receiving irinotecan also demonstrated increased clearance and lower systemic exposure. There was no difference in clearance of paclitaxel or docetaxel in smokers. Chemotherapy-associated neutropenia was worse in nonsmokers compared with smokers in patients treated with paclitaxel, docetaxel, irinotecan, and gemcitabine. CONCLUSIONS Systemic therapy for lung cancer has a narrow therapeutic index such that small changes in plasma concentrations or exposure in smokers may result in suboptimal therapy and poor outcomes. Smoking cessation must be emphasized at each clinical visit. However, prospective trials should take into consideration the effects of smoking history on drug pharmacokinetics and efficacy. The metabolizing enzyme phenotype in smokers may require individualized dose algorithms for specific agents.
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Underner M, Peiffer G, Perriot J. Prise en charge du tabagisme. REVUE DES MALADIES RESPIRATOIRES ACTUALITÉS 2014; 6:320-334. [DOI: 10.1016/s1877-1203(14)70585-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Hawari FI, Obeidat NA, Ayub HS, Dawahrah SS, Hawari SF. Smoking cessation treatment and outcomes in medium to heavy cigarette smokers being treated for cancer in Jordan. Asian Pac J Cancer Prev 2014; 14:6875-81. [PMID: 24377503 DOI: 10.7314/apjcp.2013.14.11.6875] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Studies evaluating smoking cessation treatment outcomes in cancer patients are scarce, despite smoking cessation importance in cancer care. We sought to add to the literature by evaluating smoking cessation in a challenging group of cancer patients (medium-to-heavy smokers) visiting an out-patient smoking cessation clinic (SCC) in a cancer center in Amman, Jordan. MATERIALS AND METHODS Patients smoking >9 cigarettes per day (CPD) and referred to the SCC between June 2009 and May 2012 were studied. Clinic records were reviewed to measure demographic and baseline clinical characteristics, and longitudinal (3-, 6- and 12- month) follow- up by phone/clinic visit was conducted. At each follow-up, patients were asked if they experienced medication side-effects, if they had returned to smoking, and reasons for failing to abstain. Descriptive and multivariable logistic regression analyses were performed. RESULTS A total of 201 smokers were included in the analysis. The 3-month abstinence was 23.4% and significantly associated with older age, being married, and presenting with lower (≤ 10 ppm) baseline carbon monoxide (CO) levels. On a multivariable level, lower CO levels, a higher income (relative to the lowest income group), being older, and reporting severe dependence (relative to dependence reported as 'somewhat' or 'not') were significant predictors of higher odds of abstinence at three months. Reasons for failing to quit included not being able to handle withdrawal and seeing no value in quitting. Long- term ARs did not reach 7%. CONCLUSIONS In a sample of Jordanian smokers (>9CPD) with cancer and receiving smoking cessation treatment, ARs were low and further declined with time. Results underscore the need for more aggressive patient management and rigorous follow-up during and after smoking cessation treatment, particularly when this takes place in challenging settings. Observed reasons for failure to abstain should be used to tailor counseling practices.
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Thymidine phosphorylase gene variant, platelet counts and survival in gastrointestinal cancer patients treated by fluoropyrimidines. Sci Rep 2014; 4:5697. [PMID: 25027354 PMCID: PMC4100023 DOI: 10.1038/srep05697] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 06/23/2014] [Indexed: 02/08/2023] Open
Abstract
The predictive value of thymidine phosphorylase gene variants (TP, also called platelet-derived endothelial cell growth factor) and thrombocytosis were controversial and worthy of further study in gastrointestinal cancer (GIC) patients. We screened all of the common missense single nucleotide polymorphisms (MAF ≥ 0.1) in fluoropyrimidines (FU) pathway genes (including TP, TS, ENOSF1 and DPD). Three of them were selected and genotyped using Sequenom MassARRAY in 141 GIC patients. TP expression was assessed by immunohistochemistry. Our aim was to evaluate the prognostic significance of studied genes and platelet counts in GIC patients. Multivariate analyses indicated in rs11479-T allele carriers, platelet counts negatively correlated to overall survival. In addition, T allele of TP: rs11479 was associated with higher TP expression in cancer tissues. We suggest TP: rs11479 variant combined with platelet counts may be useful prognostic makers in GIC patients receiving first-line FU chemotherapy and thrombopoietin factor should be used with caution in the rs11479 T allele bearing patients.
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O'Malley SS, Wu R, Mayne ST, Jatlow PI. Smoking cessation is followed by increases in serum bilirubin, an endogenous antioxidant associated with lower risk of lung cancer and cardiovascular disease. Nicotine Tob Res 2014; 16:1145-9. [PMID: 24812024 DOI: 10.1093/ntr/ntu067] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
INTRODUCTION Lower concentrations of serum bilirubin, an endogenous antioxidant, have been associated with risk of many smoking-related diseases, including lung cancer and cardiovascular disease, and current smokers are reported to have lower bilirubin levels than nonsmokers and past smokers. This study evaluates the effects of smoking cessation on bilirubin levels. METHODS In a secondary analysis of a 6-week placebo-controlled trial of naltrexone for smoking cessation, indirect and total bilirubin concentrations were evaluated at baseline and following smoking cessation. Individuals who were continuously abstinent for 6 weeks (n = 155) were compared to those who were not (n = 193). Participants reported smoking ≥ 20 cigarettes daily at baseline and received smoking cessation counseling, 21 mg nicotine patch daily, and either placebo or 1 of 3 doses of naltrexone (25, 50, or 100mg) for 6 weeks. Change in indirect and total bilirubin following the quit date was measured at Weeks 1, 4, and 6 compared to baseline. RESULTS Individuals who were continuously abstinent from smoking, independent of naltrexone condition, showed a significantly greater mean increase in indirect (~unconjugated) bilirubin (0.06 mg/dl, SD = 0.165) compared to those who did not (mean = 0.02, SD = 0.148, p = .015). Similar results were obtained for total bilirubin (p = .037). CONCLUSIONS Smoking cessation is followed by increases in bilirubin concentration that have been associated with lower risk of lung cancer and cardiovascular disease.
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Affiliation(s)
- Stephanie S O'Malley
- Department of Psychiatry, Yale School of Medicine, New Haven, CT; Yale Comprehensive Cancer Center, New Haven, CT;
| | - Ran Wu
- Department of Psychiatry, Yale School of Medicine, New Haven, CT
| | - Susan T Mayne
- Yale Comprehensive Cancer Center, New Haven, CT; Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT
| | - Peter I Jatlow
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT
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Mathijssen RHJ, Sparreboom A, Verweij J. Determining the optimal dose in the development of anticancer agents. Nat Rev Clin Oncol 2014; 11:272-81. [PMID: 24663127 DOI: 10.1038/nrclinonc.2014.40] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Identification of the optimal dose remains a key challenge in drug development. For cytotoxic drugs, the standard approach is based on identifying the maximum tolerated dose (MTD) in phase I trials and incorporating this to subsequent trials. However, this strategy does not take into account important aspects of clinical pharmacology. For targeted agents, the dose-effect relationships from preclinical studies are less obvious, and it is important to change the way these agents are developed to avoid recommending drug doses for different populations without evidence of differential antitumour effects in different diseases. The use of expanded cohorts in phase I trials to better define MTD and refine dose optimization should be further explored together with a focus on efficacy rather than toxicity-based predictions. Another key consideration in dose optimization is related to interindividual pharmacokinetic variability. High variability in intra-individual pharmacokinetics has been observed for many orally-administered drugs, especially those with low bioavailability, which might complicate identification of dose-effect relationships. End-organ dysfunction, interactions with other prescription drugs, herbal supplements, adherence, and food intake can influence pharmacokinetics. It is important these variables are identified during early clinical trials and considered in the development of further phase II and subsequent large-scale phase III studies.
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Affiliation(s)
- Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, Netherlands
| | - Alex Sparreboom
- Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Jaap Verweij
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE Rotterdam, Netherlands
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Moriya H, Saito K, Helsby N, Sugino S, Yamakage M, Sawaguchi T, Takasaki M, Kato H, Kurosawa N. Association between the low-dose irinotecan regimen-induced occurrence of grade 4 neutropenia and genetic variants of UGT1A1 in patients with gynecological cancers. Oncol Lett 2014; 7:2035-2040. [PMID: 24932285 PMCID: PMC4049750 DOI: 10.3892/ol.2014.2046] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 02/20/2014] [Indexed: 12/14/2022] Open
Abstract
The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22-38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.
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Affiliation(s)
- Hiroyuki Moriya
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
| | - Katsuhiko Saito
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
| | - Nuala Helsby
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Shigekazu Sugino
- Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Michiaki Yamakage
- Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takeru Sawaguchi
- Department of Pharmacy, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Masahiko Takasaki
- Department of Pharmacy, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Hidenori Kato
- Department of Gynecology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Nahoko Kurosawa
- Department of Pharmacy, Hokkaido Pharmaceutical University School of Pharmacy, Otaru, Japan
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