骨肉瘤和血液恶性肿瘤患者对进行大剂量甲氨蝶呤个体化用药的意愿调查
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摘要
目的调查患者对大剂量甲氨蝶呤个体化用药的认知与意愿,为该药临床治疗指南推荐意见的形成提供患者偏好依据。方法采用多中心横断面研究方法,以问卷形式调查7家医院骨肉瘤和血液恶性肿瘤患者对甲氨蝶呤相关基因(MTHFR C677T、MTHFR A1298C、ABCB1 C3435T、RFC1 G80A)多态性检测和治疗药物监测(TDM)的认知与意愿。统计分析采用SPSS 24.0软件进行分析。结果共纳入124例患者,包括骨肉瘤患者40例(32.26%),血液恶性肿瘤患者84例(67.74%)。124例患者中,106例(85.48%)愿意进行甲氨蝶呤相关基因多态性检测;117例(94.35%)患者愿意进行甲氨蝶呤TDM,其中存在甲氨蝶呤使用危险因素的患者与未发现甲氨蝶呤使用危险因素的患者对于接受TDM的意愿存在显著差异(76.19%vs. 95.08%,P=0.003)。患者上述2个决策的影响因素排序均有统计学上的一致性(P<0.01),并且2个决策的影响因素排序一致,治疗有效性均是患者决策时最看重的因素(秩均值分别为3.45、3.52),然后依次是安全性(秩均值分别为3.01、3.16)、舒适程度(秩均值分别为1.73、1.79),花费是对患者决策影响最小的因素(秩均值分别为1.39、1.31)。结论患者对大剂量甲氨蝶呤相关基因检测和TDM的意愿大体相似,接受度均较好。不同人群对进行甲氨蝶呤相关基因检测的意愿不存在明显差异,但甲氨蝶呤危险因素存在与否对是否进行甲氨蝶呤TDM的意愿存在明显影响,此因素可能影响临床医师与临床药师的临床治疗决策。在形成指南推荐意见和临床实践过程中应充分考虑患者的认知与意愿。
Objectives To analyze patients' values and preferences on individualized medication of high-dose methotrexate so as to support the development of the practice guideline for clinical medication of high-dose methotrexate.Methods A multicenter cross-sectional study involving patients with osteosarcoma or hematological malignancy in 7 hospitals was conducted by questionnaires to evaluate the perception and willingness on detection of gene polymorphisms(MTHFR C677 T, MTHFR A1298 C, ABCB1 C3435 T and RFC1 G80 A) related to methotrexate(MTX) and therapeutic drug monitoring(TDM) of MTX. SPSS24.0 software was used to analyze the data. Results A total of 124 patients were involved, including 40(32.26%) with osteosarcoma and 84(67.74%) with hematological malignancy. 106(85.48%) and117(94.35%) patients agreed on detection of gene polymorphisms and TDM, respectively. There was a significant difference on preference towards TDM between patients with risk factors for MTX and patients in which risk factors for MTX were not discovered(76.19% vs. 95.08%, P=0.003). The ranking of factors that contributed to the two decision-making was consistent(P<0.01), and specific orders of factors were identical. The clinical efficacy was the primary factor(mean rank 3.45 for detection of genetic polymorphisms and 3.52 for TDM), followed by safety(mean rank3.01 and 3.16, respectively) and comfort(mean rank 1.73 and 1.79, respectively). Cost(mean rank 1.39 and 1.31,respectively) was the least important factor. Conclusions The preferences of patients toward detection of gene polymorphisms and TDM were generally similar, with well acceptance. No significant differences were found on the preferences toward detection of gene polymorphisms. However, patients with or without risk factors for MTX may differ significantly when making decisions on TDM, which may impact on clinical decision-making of clinicians and clinical pharmacists. The perception and willingness of patients should be considered adequately during the development of clinical practice guidelines and clinical practice.
Objectives To analyze patients' values and preferences on individualized medication of high-dose methotrexate so as to support the development of the practice guideline for clinical medication of high-dose methotrexate.Methods A multicenter cross-sectional study involving patients with osteosarcoma or hematological malignancy in 7 hospitals was conducted by questionnaires to evaluate the perception and willingness on detection of gene polymorphisms(MTHFR C677 T, MTHFR A1298 C, ABCB1 C3435 T and RFC1 G80 A) related to methotrexate(MTX) and therapeutic drug monitoring(TDM) of MTX. SPSS24.0 software was used to analyze the data. Results A total of 124 patients were involved, including 40(32.26%) with osteosarcoma and 84(67.74%) with hematological malignancy. 106(85.48%) and117(94.35%) patients agreed on detection of gene polymorphisms and TDM, respectively. There was a significant difference on preference towards TDM between patients with risk factors for MTX and patients in which risk factors for MTX were not discovered(76.19% vs. 95.08%, P=0.003). The ranking of factors that contributed to the two decision-making was consistent(P<0.01), and specific orders of factors were identical. The clinical efficacy was the primary factor(mean rank 3.45 for detection of genetic polymorphisms and 3.52 for TDM), followed by safety(mean rank3.01 and 3.16, respectively) and comfort(mean rank 1.73 and 1.79, respectively). Cost(mean rank 1.39 and 1.31,respectively) was the least important factor. Conclusions The preferences of patients toward detection of gene polymorphisms and TDM were generally similar, with well acceptance. No significant differences were found on the preferences toward detection of gene polymorphisms. However, patients with or without risk factors for MTX may differ significantly when making decisions on TDM, which may impact on clinical decision-making of clinicians and clinical pharmacists. The perception and willingness of patients should be considered adequately during the development of clinical practice guidelines and clinical practice.
引文
1Evidence-Based Medicine Working Group.Evidence-based medicine.A new approach to teaching the practice of medicine.JAMA,1992,268(17):2420-2425.
2Sackett DL,Rosenberg WM,Gray JA,et al.Evidence based medicine:what it is and what it isn't.BMJ,1996,312(7023):71-72.
3Richardson PE.David Sackett and the birth of evidence based medicine:how to practice and teach EBM.BMJ,2015,350:h3089.
4Institute of Medicine(US)Committee on standards for developing trustworthy clinical practice guidelines;Graham R,Mancher M,Miller Wolman D,Greenfield S,Steinberg E,editors.Clinical Practice Guidelines We Can Trust.Washington(DC):National Academies Press(US);2011.
5张亮.重症医学-十年循证带给我们的启示.中华医学信息导报,2012,27(11):12.
6倪伟建,方焱,张善堂,等.基于药物基因组学与血药浓度监测指导的个体化用药研究.中国医院药学杂志,2018,38(17):1863-1868.
7Moran S,Martinez-Cardús A,Boussios S,et al.Precision medicine based on epigenomics:the paradigm of carcinoma of unknown primary.Nat Rev Clin Oncol,2017,14(11):682-694.
8Howard SC,Mc Cormick J,Pui CH,et al.Preventing and managing toxicities of high-dose methotrexate.Oncologist,2016,21(12):1471-1482.
9Mikkelsen TS,Thorn CF,Yang JJ,et al.Pharm GKB summary:methotrexate pathway.Pharmacogenet Genomics,2011,21(10):679-686.
10魏来临,张岩,邢冰.疾病诊疗决策中如何具体融合患者的价值观.医学与哲学(临床决策论坛版),2008,(8):1-2,12.
11李幼平,李静,孙鑫,等.循证医学在中国的起源与发展:献给中国循证医学20周年.中国循证医学杂志,2016,16(1):2-6.
12丁泓帆,杨楠,邓围,等.WHO指南制定的基本原则和方法.中国循证医学杂志,2016,16(4):471-477.
13Preference Collaborative Review Group.Patients'preferences within randomised trials:systematic review and patient level metaanalysis.BMJ,2008,337:a1864.
14王明辉,张菁,曾宪涛,等.临床实践指南制订方法-患者的价值观和意愿.中国循证心血管医学杂志,2018,10(10):1153-1156,1161.
15解染,徐晓涵,陈恳,等.感染患者关于万古霉素治疗药物监测的价值观与意愿调查(英文).药物流行病学杂志,2016,(6):390-395.
16徐晓涵,陈恳,孙浩,等.真菌感染患者对伏立康唑个体化用药的意愿调查.中国临床药理学杂志,2017,33(5):456-458,466.
17Yang L,Hu X,Xu L.Impact of methylenetetrahydrofolate reductase(MTHFR)polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia:a meta-analysis.Tumour Biol,2012,33(5):1445-1454.
18Lopez-Lopez E,Martin-Guerrero I,Ballesteros J,et al.A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia.Pharmacogenomics J,2013,13(6):498-506.
19何霞.还原叶酸载体基因多态性与大剂量甲氨蝶呤药物不良反应关系的Meta分析.中国临床药理学杂志,2016,32(15):1432-1434.
20解染,陈耀龙,陈昊,等.循证指南制定中患者价值观和偏好的研究方法.中国循证医学杂志,2015,15(5):586-591.
2Sackett DL,Rosenberg WM,Gray JA,et al.Evidence based medicine:what it is and what it isn't.BMJ,1996,312(7023):71-72.
3Richardson PE.David Sackett and the birth of evidence based medicine:how to practice and teach EBM.BMJ,2015,350:h3089.
4Institute of Medicine(US)Committee on standards for developing trustworthy clinical practice guidelines;Graham R,Mancher M,Miller Wolman D,Greenfield S,Steinberg E,editors.Clinical Practice Guidelines We Can Trust.Washington(DC):National Academies Press(US);2011.
5张亮.重症医学-十年循证带给我们的启示.中华医学信息导报,2012,27(11):12.
6倪伟建,方焱,张善堂,等.基于药物基因组学与血药浓度监测指导的个体化用药研究.中国医院药学杂志,2018,38(17):1863-1868.
7Moran S,Martinez-Cardús A,Boussios S,et al.Precision medicine based on epigenomics:the paradigm of carcinoma of unknown primary.Nat Rev Clin Oncol,2017,14(11):682-694.
8Howard SC,Mc Cormick J,Pui CH,et al.Preventing and managing toxicities of high-dose methotrexate.Oncologist,2016,21(12):1471-1482.
9Mikkelsen TS,Thorn CF,Yang JJ,et al.Pharm GKB summary:methotrexate pathway.Pharmacogenet Genomics,2011,21(10):679-686.
10魏来临,张岩,邢冰.疾病诊疗决策中如何具体融合患者的价值观.医学与哲学(临床决策论坛版),2008,(8):1-2,12.
11李幼平,李静,孙鑫,等.循证医学在中国的起源与发展:献给中国循证医学20周年.中国循证医学杂志,2016,16(1):2-6.
12丁泓帆,杨楠,邓围,等.WHO指南制定的基本原则和方法.中国循证医学杂志,2016,16(4):471-477.
13Preference Collaborative Review Group.Patients'preferences within randomised trials:systematic review and patient level metaanalysis.BMJ,2008,337:a1864.
14王明辉,张菁,曾宪涛,等.临床实践指南制订方法-患者的价值观和意愿.中国循证心血管医学杂志,2018,10(10):1153-1156,1161.
15解染,徐晓涵,陈恳,等.感染患者关于万古霉素治疗药物监测的价值观与意愿调查(英文).药物流行病学杂志,2016,(6):390-395.
16徐晓涵,陈恳,孙浩,等.真菌感染患者对伏立康唑个体化用药的意愿调查.中国临床药理学杂志,2017,33(5):456-458,466.
17Yang L,Hu X,Xu L.Impact of methylenetetrahydrofolate reductase(MTHFR)polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia:a meta-analysis.Tumour Biol,2012,33(5):1445-1454.
18Lopez-Lopez E,Martin-Guerrero I,Ballesteros J,et al.A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia.Pharmacogenomics J,2013,13(6):498-506.
19何霞.还原叶酸载体基因多态性与大剂量甲氨蝶呤药物不良反应关系的Meta分析.中国临床药理学杂志,2016,32(15):1432-1434.
20解染,陈耀龙,陈昊,等.循证指南制定中患者价值观和偏好的研究方法.中国循证医学杂志,2015,15(5):586-591.