低剂量节拍化疗
Review
Low-dose metronomic chemotherapy:A systematic literature analysis
K.Lien a ,S.Georgsdottir a ,L.Sivanathan a ,b ,K.Chan a ,U.Emmenegger a ,b ,?
a Division of Medical Oncology,Odette Cancer Centre,Sunnybrook Health Sciences Centre,University of Toronto,Canada
b
Sunnybrook Research Institute,Molecular and Cellular Biology Platform,Sunnybrook Health Sciences Centre,University of Toronto,Canada
Available online 20July 2013
KEYWORDS
Metronomic chemotherapy Low-dose chemotherapy Anti-angiogenesis Systematic review
Abstract
Low-dose metronomic (LDM)chemotherapy,the frequent and continuous use of
low doses of conventional chemotherapeutics,is an emerging alternative to conventional che-motherapy.While promising tumour control rates and excellent safety pro?les have been observed,there are no de?nitive phase III trial results.Furthermore,the selection of patients,drug dosages and dosing intervals is empirical.To systematically review the current state of knowledge regarding LDM chemotherapy,we searched the MEDLINE,EMBASE,CEN-TRAL and PubMed databases for fully published LDM chemotherapy trials.We calculated the relative dose-intensity (RDI,mg/m 2/week)of each LDM regimen as compared to conven-tional maximum tolerated dose (MTD)dosages and the ‘dosing-density’(DD,%of days with chemotherapy administration per cycle).Meta-regression was performed to examine factors associated with disease control rate (DCR;complete response (CR)+partial response (PR)+stable disease (SD)).Eighty studies involving mainly pretreated patients with advanced/metastatic breast (26.25%)and prostate (11.25%)cancers were retrieved.The most commonly used drug was cyclophosphamide (43%).LDM chemotherapy was frequently com-bined with other therapies (64.5%).Response rate (RR)and progression-free survival (PFS)were the most frequent primary end-points (24%and 19%).Mean RR was 26.03%(95%con-?dence interval (CI):21.4–30.7),median PFS was 4.6months (interquartile range (IQR):2.9–7.0)and mean DCR was 56.3%(95%CI:50.9–61.6).RDI,DD and metronomic drug used were not associated with DCR.Grade 3/4adverse events were rare (anaemia 7.78%,fatigue 13.4%).Thus,LDM therapy appears to be clinically bene?cial and safe in a broad range of tumors.However,meta-regression analysis did not identify predictive factors of response.ó2013Elsevier Ltd.All rights reserved.
1.Introduction
Low-dose metronomic (LDM)chemotherapy is emerging as a novel form of chemotherapy utilization,de?ned as the frequent administration of conventional
0959-8049/$-see front matter ó2013Elsevier Ltd.All rights reserved.https://www.sodocs.net/doc/ed14023028.html,/10.1016/j.ejca.2013.06.038
?Corresponding author:Address:Division of Medical Oncology,
Odette Cancer Centre,Sunnybrook Health Sciences Centre,University of Toronto,2075Bayview Avenue,Toronto,ON M4N3M5,Canada.E-mail address:urban.emmenegger@sunnybrook.ca (U.Emme-negger).
chemotherapy drugs at low doses with no prolonged drug-free breaks.1The term metronomic chemotherapy was originally coined in an editorial published in2000 by Hanahan et al.2in which the authors comment on two pivotal preclinical studies that have laid the scien-ti?c ground for LDM chemotherapy.3,4Its mechanism of action is regarded as primarily anti-angiogenic in nat-ure,a?ecting both the endothelial cells of tumour sup-plying blood vessels as well as circulating endothelial progenitor cells.In addition,recent evidence points to the presence of immunomodulatory anti-tumour activi-ties in LDM therapy.However,the importance of such immunological and other direct anti-cancer cell e?ects (such as the interference with the hypoxia-induced fac-tor1a pathway and the targeting of cancer stem cells) remains undetermined.5–8
LDM chemotherapy is associated with lower treat-ment related toxicity than conventional maximum toler-ated dose(MTD)chemotherapy.9This advantage is attractive in clinical practice when considering patients with residual toxicity from previous treatment or those who may not be considered?t for MTD chemotherapy, such as the elderly and frail.10Furthermore,the cost of a metronomic regimen may be lower than MTD chemo-therapy,as a result of fewer side-e?ect associated expen-ditures and the usage of inexpensive oral drugs such as cyclophosphamide.11
As many phase II studies have shown the clinical ben-e?ts of LDM chemotherapy,including promising tumour control rates and excellent safety pro?les,5its popularity continues to increase worldwide.For exam-ple,a recent survey of oncologists in Italy indicates that 72%of survey respondents have prescribed LDM che-motherapy at least once.12While de?nitive phase III trial results are pending,the usage of metronomic-like chemotherapy regimens has been shown to improve overall survival(OS)in phase III trials of early lung and breast cancer.13,14Currently,there are at least six randomised phase III trials in either the adjuvant set-ting,in patients with advanced cancer,in the elderly and frail,and as a maintenance treatment strategy fol-lowing conventional induction chemotherapy [https://www.sodocs.net/doc/ed14023028.html,].5,15
Many aspects of LDM chemotherapy are empirical or unresolved.These include patient selection,the choice of cytotoxic drug used for treatment,its optimal dose and dosing interval and the nature of other treatment modalities often co-administered.5,6,9On average,single doses in LDM regimens tend to be in the range of one tenth to one third of the MTD dose.1,16Other questions include the bene?ts of doublet versus single agent LDM chemotherapy and whether or not treatment e?cacy depends on the tumour type.This systematic review aims to evaluate all fully published LDM chemotherapy trials in adults in an attempt to answer the questions raised above.2.Materials and methods
2.1.Search strategy
The MEDLINE,EMBASE and CENTRAL dat-abases were searched for fully published articles using the key words‘metronomic’and‘chemotherapy’and ‘cancer’or‘neoplasm’or‘tumour’.The search was restricted to English language clinical trials from2000 to April2012inclusive.Exclusion criteria included the following:purely translational(companion)studies, paediatric trials,trials with less than20patients,studies applying MTD or near-MTD chemotherapy doses,edi-torials and review articles.An additional PubMed search using the term‘metronomic chemotherapy’,lim-ited to English language publications from any time up to and including April2012,was performed to retrieve any additional articles.A manual search was performed to retrieve relevant studies referenced in the publications identi?ed from the original search.For studies with mul-tiple presentations and/or publications,only the latest versions were included in the analysis.
2.2.Data abstraction and statistical analyses
Two reviewers independently extracted information on study designs,tumour types investigated,patient demographics,regimens applied,e?cacy criteria used and reported safety data.Discrepancies were adjudi-cated by a third reviewer.The absolute dose-intensity (DI,mg/m2/week)17of each LDM regimen was calcu-lated and used to obtain the relative dose-intensity (RDI)as compared to the DI of the same agent used in an MTD manner.The MTD DI for a given drug was calculated using data from the Cancer Care Ontario Drug Formulary,unless otherwise indicated(Supple-mentary Table1).We assumed that the average body surface area of an adult patient was1.8m2based on data from the literature.18,19We also calculated the dos-ing-density(DD),de?ned as the%of days with LDM chemotherapy administration per cycle of treatment. In the event that more than one chemotherapy drug was used metronomically,the DIs were totalled to give a single value for the speci?ed treatment regimen;the same calculation applied for DDs.The DD was then categorised as either greater or equal to100%(signifying continuous daily treatment with at least one chemother-apy drug)or less than100%.
Meta-regression analysis using mixed-e?ect logistic regression(SAS version9.3,Cary,NC,United States of America(USA))to account for clustering of patients and outcomes within studies was performed to examine factors associated with disease control rate(DCR), de?ned as complete response(CR)+partial response (PR)+stable disease(SD).Factors that were consid-ered included RDI,DD,regimen type(singlet LDM,
3388K.Lien et al./European Journal of Cancer49(2013)3387–3395
or doublet LDM,or singlet LDM and another treat-ment,or doublet LDM and another treatment),cancer type(breast cancer,prostate cancer,lung cancer or other cancers)and metronomic drug(s)used(cyclophos-phamide,?uoropyrimidines,cyclophosphamide with de-duplication and application of the exclusion criteria, 576studies were removed.The manual reference search did not provide any additional publications.Eighty studies were selected for our analysis;the complete list of references is available in Supplementary Table2.
Fig.1.Flow diagram of search strategies.
K.Lien et al./European Journal of Cancer49(2013)3387–33953389
addition of LDM chemotherapy to targeted therapy (n =2),the addition of targeted therapy to LDM che-motherapy (n =2),LDM monotherapy compared to a targeted agent (n =1),MTD chemotherapy versus LDM chemotherapy using the same drug (n =1)and targeted therapy in combination with one of two di?er-ent cytotoxic agents (n =1).Non-randomised multi-arm trials tested the same clinical scenarios (n =7),in addi-tion to examining the e?ect of LDM chemotherapy on patients with di?erent treatment histories (n =1)and on patients with di?erent cancer types (n =1).Twelve publications were retrospective chart reviews;the most common amongst these were retrospective studies on prostate cancer (n =5).
72.5%of the studies had patient sample sizes of less than 50,and the median number of subjects enrolled was 40(range =20–178).Breast,prostate and lung can-cer studies were the most common;their sample sizes account for almost half of all patients (48%)(Table 1).A limited number of studies were in the adjuvant (n =3)or neoadjuvant (n =2)settings.Of the 75studies focused on metastatic or advanced cancers,47included patients with any number of prior lines of systemic treat-ment.Fifty three studies (66%)required patients to have an Eastern Cooperative Oncology Group (ECOG)per-formance status 62.3.3.Metronomic regimens
In total,107treatment regimens with at least one metronomically used drug were identi?ed.The most fre-quently used LDM drugs were cyclophosphamide,cape-citabine,etoposide and vinorelbine (Table 2).If more than one cytotoxic agent was used metronomically in a regimen,all were counted.Thirty eight regimens used LDM chemotherapy only (monotherapy:n =24,dou-blet LDM therapy:n =14).The RDI of LDM mono-therapy regimens ranged from 0.27to 1.58(median:1.02);DD ranged from 32%to 100%(median:100%)(Fig.3A).In doublet LDM,RDI ranged from 0.33to
1.67(median:0.63)and DD from 57%to 200%(median:128.57%)(Fig.3B).Doublet LDM therapy typically combined cyclophosphamide and methotrexate (n =12).Metronomically used drugs were frequently adminis-tered with the same or other chemotherapeutic drugs used at their MTD (n =12).Fifty seven (53%)regimens used LDM chemotherapy in combination with other anti-cancer agents such as bevacizumab,celecoxib,prednisone and
thalidomide.
Fig.2.(A)Low-dose metronomic (LDM)studies published per year from 2002until April 2012.(B)Number of LDM studies per country and (C)per 10million residents.
Table 1
Study demographics.Demographics Number of publications (%)N =80
Number of patients (%)N =3688
Number of patients 20–2510(12.5)26–3015(18.75)31–359(11.25)36–407(8.75)41–4510(12.5)46–507(8.75)51–607(8.75)61–707(8.75)71–801(1.25)80–1003(3.75)>100
4(5.0)Tumour type Breast
21(26.25)1135(30.8)Miscellaneous 9(11.25)457(12.4)Prostate 9(11.25)322(8.7)Lung 7(8.75)317(8.6)Blood 6(7.5)230(6.2)Brain
6(7.5)373(10.1)Colorectal 4(5.0)154(4.2)Skin 4(5.0)164(4.4)Liver 3(3.75)126(3.4)Adrenal 2(2.5)53(1.4)Soft tissue
2(2.5)52(1.4)Gastrointestinal 2(2.5)83(2.3)Kidney 2(2.5)85(2.3)Ovary
2(2.5)108(2.9)Neuroendocrine
1(1.25)
29(0.8)
3.4.Outcomes
Response rate (RR),progression free survival (PFS)and safety assessment were the most frequent primary end-points (Table 3).If more than one primary end-point was de?ned by the study protocol,they were included separately in our analysis.Response rates were obtained using various criteria according to the type of tumour studied (Table 3).Without strati?cation for Table 2
Metronomic drugs.Metronomic drug Number of regimens used (%)N =107Cyclophosphamide 46(43.0)Capecitabine 15(14.0)Etoposide 15(14.0)Vinorelbine 15(14.0)Methotrexate 12(11.2)Temozolomide
9(8.4)Tegafur and uracil (UFT)6(5.6)Trofosfamide 5(4.7)Procarbazine
3(2.8)5-Fluorouracil (5-FU)2(1.9)Carboplatin
2(1.9)Irinotecan (CPT-11)2(1.9)Docetaxel 2(1.9)Paclitaxel 2(1.9)Vinblastine 2(1.9)Carboplatin 1(0.9)Doxi?uridine 1(0.9)Mitomycin C
1(0.9)
Fig.3.(A)Relative dose-intensity and dosing-density of LDM monotherapy and of (B)LDM doublet therapy by regimen.Data not presented for doublet LDM regimen due to varying dosage levels used.
Table 3
Common primary end-points.
Number of publications (%)N =80Primary end-point
Response rate (complete response (CR)+partial response (PR))19(23.75)Progression free survival 15(18.75)Safety
12(15.0)Not applicable
7(8.75)Clinical bene?t rate 6(7.5)Overall survival 6(7.5)PSA response a
6(7.5)Time to progression 4(5.0)E?cacy 4(5.0)Activity
4(5.0)Miscellaneous b 16(20.0)Response criteria RECIST c 47(58.75)WHO 13(16.25)Cheson 4(5.0)PSA c
3(3.75)Macdonald d 3(3.75)Other
10(12.5)
Abbreviations:PSA,prostate-speci?c antigen;RECIST,Response Evaluation Criteria in Solid Tumours;WHO,World Health Organisation.a
Prostate Cancer Clinical Trials Working Group.b
Includes:tolerance,pathological response,toxicity,stable disease,circulating endothelial cell (CEC)enumeration,adverse and biological events,pharmacodynamic end-points,disease control rate,vascular endothelial growth factor (VEGF)reduction and feasibility.c
Prostate Cancer Clinical Trials Working Group and other de?nitions.K.Lien et al./European Journal of Cancer 49(2013)3387–3395
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(p =0.37).The multivariable mixed-e?ect model,taking into account all the factors above,did not reveal any statistical associations between DCR with any of the above factors adjusting for the rest of the factors.3.6.Adverse events
The majority of studies used the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE,any version),while 7used the World Health Organisation (WHO)criteria.Nine studies did not specify the criteria used to de?ne toxicities or did not report adverse events using grade levels.For four of the 107regimens,no toxicity ?ndings were reported.Table 4describes the occurrence of severe (i.e.grade 3or 4)adverse events.Any rate of severe haematological toxicity was recorded,while non-haematological toxicity rates were included only if they occurred in greater than 5%of patients.Twenty four regimens did not result in any severe haematological side-e?ects,of which 17also
Fig.4.(A)Range of median progression free survival reported for 52treatment arms.(B)Range of response rates reported for 89treatment arms.
Fig.5.(A)Range of disease control rates and of (B)clinical bene?t rates reported in 89and 36treatment arms,respectively.
Table 4
Adverse events.Grade 3or 4Number of patients a?ected (%)N =3688Haematological Neutropenia 199(5.39)Lymphopenia 144(3.91)Leucopenia 111(3.01)Anaemia
64(1.73)Thrombocytopenia 53(1.44)Febrile neutropenia 20(0.53)Non-haematological Fatigue
72(1.95)Transaminases
68(1.84)Hand-foot syndrome 31(0.84)Thrombosis
22(0.59)Colitis/mucositis/stomatitis 21(0.57)Nausea/vomiting 21(0.57)Infection 18(0.50)Neurological 17(0.47)Diarrhoea 14(0.38)Hypertension
13(0.35)
had no grade3or4non-haematological toxicity preva-lent in more than5%of patients.As expected of LDM chemotherapy,low toxicity rates were observed.No tox-icity a?ected more than6%of all pooled patients.Over-all,15treatment related deaths were recorded(0.4%).
4.Discussion
Since the beginning of the era of chemotherapy more than70years ago,the usage of chemotherapeutic agents has undergone a number of transformations,including the development of the MTD concept,of combination regimens and more recently,of dose-dense administra-tion protocols.21Improved supportive care measures have enabled medical oncologists to prescribe increas-ingly higher doses of chemotherapy in an attempt to optimise tumour cell destruction.On the other hand, this‘more is better’approach has masked some of the more subtle e?ects of chemotherapy,such as its various anti-vascular activities.22
Regular MTD dosing is characterised by cyclic bolus chemotherapy administration at the MTD,with inter-spersed drug-free periods to allow for patient recovery from treatment-associated side-e?ects.Alternatively, continuous intravenous or oral chemotherapy has been studied since around50years in various clinical set-tings.23,24While such chronic treatment protocols were still guided by the MTD concept,the use of5-?uoroura-cil exempli?es that bolus versus continuous chemother-apy administration can a?ect the biological e?ect pro?le of chemotherapy agents.25Furthermore,recent preclinical studies revealed that such continuous regi-mens might emphasise the anti-vascular e?ects of che-motherapy drugs compared to conventional MTD scheduling.3,4Of note,these studies also suggested that potent anti-vascular e?ects could be achieved without the need for dosing to dose-limiting toxicities.
A pragmatic de?nition of LDM chemotherapy com-prises of three major elements:(1)frequent,(2)long-term,uninterrupted drug administration at(3)minimal dosage levels,avoiding the overt bone marrow suppres-sion observed in MTD administration,which has been shown to cause the mobilisation of bone marrow derived cells with pro-angiogenic functions.1,6,16Mathe-matical modelling suggests that the optimal metronomic administration frequency should be guided by maintain-ing an anti-angiogenic threshold drug concentration.26 Based on the degree of suppression of endothelial pro-genitor cells versus myelosuppression,Shaked et al.have described a method to determine the optimal LDM dose in mice.27However,this method is not suitable for clin-ical purposes for a number of reasons,including the paucity of endothelial progenitor cells in cancer patients compared to mice.28In addition,although Takahashi et al.have described a conceptually similar method suit-able for clinical use,i.e.the individualised maximum repeatable dose,this approach has not been adopted up to date for LDM trials.29
Given that many clinical aspects of LDM therapy are still empirical,we decided to undertake this systematic analysis of LDM trials to synthesise the current litera-ture on the subject.Overall,we show that LDM chemo-therapy is increasingly popular,and that it has bene?cial activity in a broad range of tumour types,while retain-ing a low occurrence of severe side-e?ects.Clinical prac-tice patterns,the variable funding structures of the health systems or even academic leadership may explain, amongst other reasons,why LDM trial activities vary considerably according to geographic location.Our analysis of more than a hundred treatment arms also reveals signi?cant heterogeneity in what is considered LDM chemotherapy.The mean RR of the pooled treat-ment regimens was26.03%,with a mean DCR of56.3%. Responses lasted4.6months on average.Aside from a grade3/4neutropenia rate of5.39%,other severe side-e?ects were seen in less than5%of patients.Possible treatment-associated fatalities were very rare(0.4%), despite the fact that most study patients presented with advanced disease,refractory to often multiple prior con-ventional systemic therapies.As such,LDM compares favourably with MTD chemotherapy and with targeted anti-vascular therapies.30–34
We did not?nd signi?cant associations between DCR and patient characteristics,the type of drug(s) used or other aspects of the LDM regimens,such as the RDI.Regarding the latter,the absence of a positive correlation between RDI and outcome is not completely unexpected.In fact,neither the biological rationale for LDM therapy nor mathematical modelling suggests a positive association between dose and response once the anti-angiogenic threshold dose is achieved.1,26On the other hand,our analyses reveal that the RDI of approximately half of the LDM regimens studied is sim-ilar to or even higher than the DI of corresponding MTD regimens.Since prolonged tumour cell exposure to cell-cycle independent agents such as cyclophospha-mide,the most commonly used drug in LDM regimens, may augment cell kill relative to bolus treatment,35it remains to be seen if studies focusing on the anti-angio-genic e?ects of LDM cyclophosphamide therapy under-estimate the possible direct anti-tumour e?ects of prolonged treatment with cyclophosphamide.Similarly, the bene?ts of sustained versus cyclic temozolomide administration may be due to both anti-angiogenic e?ects and depletion of tumour cell O6-methylguanylm-ethyltransferase activity.36
There was also no signi?cant association between outcome and the DD of LDM regimens,although math-ematical modelling studies of Hahnfeldt et al.suggest that drug administration frequency is positively associ-ated with treatment outcome.26However,DD as calcu-
K.Lien et al./European Journal of Cancer49(2013)3387–33953393
lated for our analyses did not consider pharmacokinetic aspects of individual drugs,such as their half-life.In fact,as long as the anti-angiogenic threshold drug con-centration is maintained,daily drug administration may not be necessary for certain chemotherapy agents.
To the best of our knowledge,this is the?rst system-atic literature analysis of LDM therapy.While it sum-marises the observations regarding almost3700 patients,it also has a number of limitations.As the majority of the reported data is extracted from relatively small phase II trials,there was a broad range of tumour types and LDM regimens studied.In addition,study patients were often very heterogeneous at both an indi-vidual trial level,as the number and type of prior ther-apies patients had undergone varied,and at a systematic level,considering the numerous di?erences between the80studies that were analysed.Furthermore, more than half of the regimens included treatment modalities other than LDM chemotherapy.
The results of large phase III trials designed with the metronomic concept in mind will be reported within the next few years[https://www.sodocs.net/doc/ed14023028.html,].5,15Based on our analyses,it is fair to assume that at least some of these trials will show clinical bene?t.On the other hand,these trials will unlikely provide de?nite answers regarding questions surrounding optimal metronomic dosing and administration scheduling.Nonetheless,future correla-tive companion studies may reveal potential predictive markers of response.
To summarise,phase II evidence comprising of almost3700patients indicates that LDM chemotherapy is active and can be safely administered.Further e?orts are needed to individualise the choice of chemotherapy agent(s)used and the treatment context,including the choice of concurrent treatment modalities.Amid increasing concerns about the costs of cancer therapy,37 it is attractive to consider using non-expensive drugs such as cyclophosphamide in a LDM manner.Positive phase III trial results will be crucial to encourage regu-latory authorities and industry partners for further clin-ical exploration of LDM chemotherapy.
Funding
This work was supported by a Clinician Scientist Award from Prostate Cancer Canada to UE.
Con?ict of interest statement
None declared.
Appendix A.Supplementary data
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常用化疗药分类
1.细胞周期非特异性药物（CCNSC）和细胞周期特异性药物（CCSC ）的区别 CCSC是周期特异性药物，特异性地杀伤处于特定时相的肿瘤细胞，需等肿瘤细胞处于对应时相才有效，故应慢滴。 2.化疗药物给药剂量按体表面积计算（文生氏公式） 体表面积（m2）=0.0061×身高（cm）+0.128×体重（kg）-0.1529 工作中计算体表面积：以身高1.6m，体重60公斤，体表面积为1.6m2，做调整 3.肿瘤病人治疗后，无复发，生存率≥5年，算治愈 4.联合化疗方案药物成原则 a.两种以上作用机制不同的药物组成 b.周期非特异性药物和不同时相的周期特异性药物配合 c.各药的毒性不相重复 d.一般3～4个药物最好,临床上一般2-3个药合用，4个药合用一般用于复发的肿瘤患者或者难治性的血液病患者， 5.化疗药物的器官毒性 ADR（多柔比星，阿霉素）：心脏毒性 BLM（博来霉素）：肺纤维化 DDP（顺铂）：肾毒性 L-OHP（奥沙利铂）、VCR（长春新碱）、PTX（紫杉醇）：神经毒性 BCNU（卡莫司汀）：肝毒性 6.化疗分为 a.诱导化疗:又称新辅助化疗，实施局部治疗方法（如手术或放疗）前所做的全身化疗，目的是使肿块缩小、及早杀灭看不见的转移细胞，以利于后续的手术、放疗等治疗。对于早期和晚期肿瘤患者不采用新辅助化疗的方法。 b.辅助化疗:手术治疗和放疗的后，杀灭手术无法清除的微小病灶，减少复发，提高生存率。
c.姑息化疗:对于手术后复发、转移或就诊时不能切除的肿瘤病人，目的并不是彻底地消灭肿瘤，而在于能够平稳地控制肿瘤的进展，缓解患者的痛苦，延长其生命。这时的化疗称作“姑息化疗”。 7.常用细胞周期特异性药物 S 期特异性药物： 抗叶酸类：甲氨蝶呤（MTX ，胸腺嘧啶、嘌呤）、培美曲塞（PEM ，胸腺 嘧啶、嘌呤，）、雷替曲塞（胸腺嘧啶）、六甲蜜胺（嘧啶） 抗嘧啶类：氟尿嘧啶（5-FU ）、卡培他滨（CAPE ，希罗达，5-FU 前体药）、 替加氟（FT207，5-FU 衍生物）、替吉奥（替加氟+吉美嘧啶 +奥替拉西钾）、优福定（替加氟+尿嘧啶）、卡莫氟（HCFU ， 5-FU 衍生物）、 阿糖胞苷（Ara-c ）、吉西他滨(GEM ，作用机制同Ara-c)、 安西他滨（Ara-c 衍生物） 抗嘌呤类：6-巯嘌呤（6-MP ）、硫唑嘌呤（体内转化6-巯嘌呤起作用）、 氟达拉滨（Ara-A ，阿糖腺苷类似物，抗病毒类）、硫鸟嘌呤 （6-TG ）、喷他司丁（DCF ，新的抗代谢药，本品是从链霉素 菌中分离得的抗生素） 干扰嘌呤和嘧啶合成 ：羟基脲(HU) 拓扑异构酶I ：喜树碱类，羟喜树碱（HCPT ），伊立替康（CPT-11）、 拓扑替康 拓扑异构酶II ：依托泊苷（VP-16）、替尼泊苷（VM-26） M 期特异性药物：长春碱类：长春碱（VLB ）、长春新碱（VCR ）、长春瑞滨（NVB ）、 长春地辛（VDS ） 紫杉类：紫杉醇（PTX ）、多西他赛（DOC ） G 1期特异性药物：L-ASP （L-门冬酰胺酶），肾上腺皮质类固醇 G 2期特异性药物：博来霉素（BLM ，国外）、平阳霉素 （PYM ，国内，与BLM 成 分相近） 影响蛋白质功能与合成的药 门冬酰胺酶、培门冬酶、高三尖杉酯碱 抗代谢类 拓扑异构酶抑制剂
三基培训考试肿瘤科学大剂量顺铂化疗处理
三基培训考试肿瘤科学大剂量顺铂化疗处理 (总分：6.00，做题时间：60分钟) 一、多项选择题(总题数：1，分数：1.00) 1.大剂量顺铂化疗用药期间利尿措施采用下列哪些方法：（） （分数：1.00） A.多饮水 B.应用速尿√ C.应用氨体舒通 D.应用甘露醇√ E.大量输液 解析： 二、填空题(总题数：2，分数：2.00) 2.临床上对 1、 2、 3、 4、 5的患者应慎用或不采用大剂量顺铂化疗。 （分数：1.00） 填空项1:__________________ （正确答案：年龄大） 填空项1:__________________ （正确答案：血管硬化） 填空项1:__________________ （正确答案：肾功能差） 填空项1:__________________ （正确答案：有听力障碍） 填空项1:__________________ （正确答案：对化疗消化道反应缺乏耐受） 解析： 3.大剂量顺铂化疗用药期间应给予 1、 2、 3。 （分数：1.00） 填空项1:__________________ （正确答案：水化） 填空项1:__________________ （正确答案：利尿措施） 填空项1:__________________ （正确答案：补充电解质） 解析： 三、问答题(总题数：3，分数：3.00) 4.大剂量顺铂化疗的适应证和禁忌证。 （分数：1.00） __________________________________________________________________________________________ 正确答案：(实体瘤化疗中需要使用顺铂者均可采用大剂量顺铂化疗。但对年龄大、血管硬化、肾功能差和有听力障碍及对化疗消化道反应缺乏耐受性的患者应慎用或不用大剂量顺铂化疗。) 解析： 5.试述大剂量顺铂化疗的操作要点。 （分数：1.00） __________________________________________________________________________________________ 正确答案：(大剂量顺铂化疗的操作要点为：（1）顺铂溶于生理盐水或3％氯化钠200 ml中静滴，并采用水化与甘露醇、呋塞米利尿的方法，以减轻肾脏毒性。（2）一般在应用大剂量DDP之前先补液(生理盐水或5％葡萄糖盐水注射液)1 000～2 000 ml，加10％氯化钾20 ml。DDP之后继续输液5 000 ml(每1 000 ml液体给氯化钾20 mmol)。输液从DDP给药之前12小时开始，持续到DDP滴完后24小时为止。（3）为促进利尿，输注DDP之前先快速静滴20％甘露醇125 ml，DDP之后再给予20％甘露醇125 ml快速静滴，并根据尿量适当使用速尿。（4）此疗法每3周一次，可重复3～4次。) 解析： 6.试述大剂量顺铂化疗的注意事项。 （分数：1.00）
常用化疗药分类
1、细胞周期非特异性药物（CCNSC）与细胞周期特异性药物（CCSC ）得区别 CCSC就是周期特异性药物，特异性地杀伤处于特定时相得肿瘤细胞，需等肿瘤细胞处于对应时相才有效，故应慢滴。 2.化疗药物给药剂量按体表面积计算（文生氏公式） 体表面积（m2）=0、0061×身高（cm）+0、128×体重（kg）-0、1529 工作中计算体表面积：以身高1、6m，体重60公斤，体表面积为1、6m2，做调整 3.肿瘤病人治疗后，无复发，生存率≥5年，算治愈 4.联合化疗方案药物成原则 a、两种以上作用机制不同得药物组成 b、周期非特异性药物与不同时相得周期特异性药物配合 c、各药得毒性不相重复 d、一般3～4个药物最好,临床上一般2-3个药合用，4个药合用一般用于复发得肿瘤患者或者难治性得血液病患者， 5、化疗药物得器官毒性 ADR（多柔比星，阿霉素）：心脏毒性 BLM（博来霉素）：肺纤维化 DDP（顺铂）：肾毒性 L-OHP（奥沙利铂）、VCR（长春新碱）、PTX（紫杉醇）：神经毒性 BCNU（卡莫司汀）：肝毒性 6.化疗分为 a、诱导化疗:又称新辅助化疗，实施局部治疗方法（如手术或放疗）前所做得全身化疗，目得就是使肿块缩小、及早杀灭瞧不见得转移细胞，以利于后续得手术、放疗等治疗。对于早期与晚期肿瘤患者不采用新辅助化疗得方法。 b、辅助化疗:手术治疗与放疗得后，杀灭手术无法清除得微小病灶，减少复发，提高生存率。
c 、姑息化疗:对于手术后复发、转移或就诊时不能切除得肿瘤病人，目得并不就是彻底地消灭肿瘤，而在于能够平稳地控制肿瘤得进展，缓解患者得痛苦，延长其生命。这时得化疗称作“姑息化疗”。 7、常用细胞周期特异性药物 S 期特异性药物： 抗叶酸类：甲氨蝶呤（MTX ，胸腺嘧啶、嘌呤）、培美曲塞（PEM ，胸腺 嘧啶、嘌呤，）、雷替曲塞（胸腺嘧啶）、六甲蜜胺（嘧啶） 抗嘧啶类：氟尿嘧啶（5-FU ）、卡培她滨（CAPE ，希罗达，5-FU 前体药）、 替加氟（FT207，5-FU 衍生物）、替吉奥（替加氟+吉美嘧啶 +奥替拉西钾）、优福定（替加氟+尿嘧啶）、卡莫氟（HCFU ， 5-FU 衍生物）、 阿糖胞苷（Ara-c ）、吉西她滨(GEM ，作用机制同Ara-c)、 安西她滨（Ara-c 衍生物） 抗嘌呤类：6-巯嘌呤（6-MP ）、硫唑嘌呤（体内转化6-巯嘌呤起作用）、 氟达拉滨（Ara-A ，阿糖腺苷类似物，抗病毒类）、硫鸟嘌呤 （6-TG ）、喷她司丁（DCF ，新得抗代谢药，本品就是从链霉 素菌中分离得得抗生素） 干扰嘌呤与嘧啶合成 ：羟基脲(HU) 拓扑异构酶I ：喜树碱类，羟喜树碱（HCPT ），伊立替康（CPT-11）、拓扑替康 拓扑异构酶II ：依托泊苷（VP-16）、替尼泊苷（VM-26） M 期特异性药物：长春碱类：长春碱（VLB ）、长春新碱（VCR ）、长春瑞滨（NVB ）、 长春地辛（VDS ） 紫杉类：紫杉醇（PTX ）、多西她赛（DOC ） G 1期特异性药物：L-ASP （L-门冬酰胺酶），肾上腺皮质类固醇 G 2期特异性药物：博来霉素（BLM ，国外）、平阳霉素 （PYM ，国内，与BLM 成 分相近） 影响蛋白质功能与合成得药 门冬酰胺酶、培门冬酶、高三尖杉酯碱 抗代谢类 拓扑异构酶抑制剂
急性白血病大剂量化疗的护理体会
【关键词】白血病；急性；大剂量化疗；护理 ［摘要］目的：探索急性白血病大剂量化疗相关并发症及不良反应的护理方法。方法：我院1997年6月至2004年6月共收治应用大剂量化疗的急性白血病化疗137例，根据白血病化疗中出现的不良反应如消化道反应、感染、贫血、出血、静脉炎、口腔溃疡、脏器功能损伤等的发生机制、规律、临床表现、转归进行心理、饮食、病因、发病机制对症等个性化的护理。同时选择1990年6月至1997年5月大剂量化疗的白血病患者作为对照组，比较其不良反应的护理效果。结果：经过个性化护理，急性白血病大剂量化疗后出现的消化道反应、感染、贫血、出血、静脉炎、口腔溃疡、脏器功能损伤等并发症及不良反应的发生率及恢复时间均不同程度的缩短(p<0．05)。结论：合理有效的护理对急性白血病大剂量化疗后出现的并发症及不良反应具有较好的疗效。 ［关键词］白血病；急性；大剂量化疗；护理 急性白血病是常见的血液系统恶性肿瘤，其最主要的治疗方法是大剂量化疗患者，化疗可引起一系列的毒副反应及骨髓抑制，如消化道反应、感染、贫血、出血、静脉炎、口腔溃疡、脏器功能损伤等，如处理不当可引起严重的后果，甚至导致治疗失败。我院1997年6月至2004年6月共收治急性白血病化疗患者137例，我们对其临床表现及化疗的毒副作用进行观察，并进行个性化合理护理取得了较好的效果，报告如下。 1 临床资料 1.1 一般资料 本组137例为我院1997年6月至2004年6月收治的急性白血病患者，男性78例，女性59例；年龄19岁~73岁，中位年龄43岁；急性淋巴细胞白血病(all)32例，急性非淋巴细胞白血病(anll)105例，其中m19例，m227例，m328例，m418例，m519例，m64例。同时选择1990年6月至1997年5月大剂量化疗的白血病患者142例作为对照组，两组病例入院时情况、年龄、性别、化疗方案差异无显著性，具有可比性。所有病例均符合急性白血病的诊断标准［1］。 1.2 临床表现本组病例鼻衄、牙龈及皮肤出血71例，淋巴结及肝脾肿大34例，牙龈肿胀25例，贫血91例，发热78例。脑部损害11例，转氨酶升高6例，黄疸2例，肺部感染29例，表现为咳嗽、咳痰、胸闷、气急、呼吸困难、紫绀，急性肾功能不全6例，表现为少尿或无尿、血尿素氮及肌酐增高，静脉炎23例，口腔溃疡感染35例，心衰2例。 1．3 化疗药物及方案 环磷酰胺(c)，长春新碱(o)，柔红霉素(d)，左旋门冬酰胺酶(l)，强的松(p)，阿糖胞苷(a)，胺丫啶(a)，米托蒽醌(m)，足叶乙甙(vp16、e)all应用codp(环磷酰胺+长春新碱+柔红霉素+强的松)、vdlp(长春新碱牛柔红霉素+左旋门冬酰胺酶牛强的松)方案，anll应用da(柔红霉素+阿糖胞苷)、aa(胺丫啶+阿糖胞苷)、ma(米托蒽醌+阿糖胞苷)、ha(高三尖杉酯碱+阿糖胞苷)、had(高三尖杉酯碱+阿糖胞苷+柔红霉素)、ea(足叶乙甙+阿糖胞苷)等方案。 1．4 观察方法 对137例患者的不同临床表现进行护理，根据白血病化疗中出现的不良反应如消化道反应、感染、贫血、出血、静脉炎、口腔溃疡、脏器功能损伤等的发生机制、规律、临床表现、转归进行心理、饮食、病因、发病机制对症等个性化的护理，与对照组进行比较。统计数据应用±s，应用t检验。 2 护理 2.1 静脉炎的护理措施 化疗引起的静脉炎多于化疗后数分钟至数小时出现，首先在静脉注射处出现疼痛，继而出现红肿起泡，最后坏死溃烂。如在发现药物有外渗现象后或出现静脉炎的早期及时处理，可阻止其进一步发展，防止坏死的出现，可于化疗出现静脉炎后，根据所用药物的不同，
化疗药物分类[剖析]
化疗药物分类[剖析] 化疗药物的分类 1.烷化剂 这类药物由烷基和功能基团结合而成。可与细胞中的多种有机物如DNA，RNA 或蛋白质的亲核基团(如核酸的磷酸根、羟基、氨基，蛋白质的羧酸根、巯基、氨基)结合，以烷基取代这些基团的氢原子，使这些对生命有重要意义的生化物质和核酸、酶等不能进行正常代谢。这类细胞毒性药物能与多种细胞成分起作用，增生快的细胞首先被杀伤，浓度足够大时可杀伤各种类型的细胞。其共同的缺点是选择性不强，对骨髓、消化道细胞和生殖细胞也有很强的杀伤作用。典型代表药物为氮芥和环磷酰胺等。如氮芥、卡莫司汀(卡氮芥)、环磷酰胺、白消安(马利兰)、洛莫司汀(环己亚硝脲)等。 1,尼莫司汀宁得朗 ACNU 本品25mg用注射水5ml,50mg加注射用水10ml溶解后,再用生理盐水稀释后静点或动脉注射粉针25mg50mg 2,卡莫司汀卡氮芥 BCNU 单用每次125mg加入等渗盐水或葡萄糖250ml,静脉滴注1-2h注射125mg 3,洛莫司汀环己亚硝脲 CCNU 呕吐较严重胶囊40mg100mg 4,环磷酰胺环磷氮芥 CTX 400-1000mg/m2,配后存放不应超过3h片剂50mg 注射100mg 200mg 5,异环磷酰胺异磷酰胺和乐生 IFO 单用总量7-10g/m2分3-5天肾功不全慎用. 注射0.5g1g 2g 6,甘磷酰芥 M-25 司莫司汀甲环亚硝脲 Me-CCNU 胶囊50mg 2.抗代谢药
这一类药物的结构和人体正常生理代谢的结构类似，因而可以干扰正常代谢物的功能，在核酸合成的不同水平加以阻断而产生疗效。常用的抗代谢药物分为叶酸拮抗物、嘌呤类似物、嘧啶类似物等。由于尚未发现正常细胞和肿瘤细胞蛋白代谢上的特异性差异，起效的机制在于利用了正常细胞和肿瘤细胞中碱基和酶系含量的差异，因而抗代谢药物的最大缺点是在抑制肿瘤细胞的同时对增生旺盛的正常细胞也有相当的毒性，且易发生耐药。抗代谢药物的代表药有:叶酸抗代谢药物、嘌呤抗代谢药物和嘧啶抗代谢药物。如氟尿嘧啶、甲氨喋呤、阿糖胞苷、巯基嘌呤、替加氟(呋喃氟尿嘧啶)等 2,多西氟鸟啶5’-DFUR 特别注意出血倾向.禁与抗病毒索立夫定并用. 胶囊100mg200mg 4巯嘌呤 6-巯基嘌呤 6-MP 片剂25mg50mg 6,阿糖胞苷阿糖胞嘧啶 Ara-C 常用剂量每次100mg//m2,每12h1次,共5-10天;二性霉素B或地高辛可使疗效下降注射剂50mg100mg 7,氟鸟苷氟鸟脱氧核苷 FNDR 为5-FU替代产品,疗效高2-3倍,毒性低5-6倍.主要用于肝动脉灌注法治疗原发性肝癌及结直肠癌肝转移,每次125-500mg,每日一次. 针粉剂250mg 8,替加氟喃氟定 FT-207 体内转化为5-FU,毒性较低 9,吉西他滨健择 Gemzer 可改善胰腺癌病人得生活质量.推荐剂量为 1000mg//m2静点30min,每周一次,共3次,每4周重复,多与CDDP联合. 粉针剂 200mg1000mg 禁冷藏 10,卡莫氟氟尿己胺 HCFU 11,羟基脲 HU 12,甲氨蝶呤氨甲蝶呤 MTX 注射5mg0.1g1.0g 13,优福定复方替加氟 UFT 为FT-207与尿嘧啶1:4得复方制剂
化疗药物常见分类
化疗药物种类 1.烷化剂：烷化剂直接作用于DNA上，防止癌细胞再生。此类药物对慢性白血病、恶性淋巴瘤、何杰金氏病、多发性骨髓瘤、肺癌、乳腺癌和卵巢癌具有疗效。 2.抗代药：抗代药干扰DNA和RNA的合成，用于治疗慢性白血病、乳腺癌、卵巢癌、胃癌和结直肠癌。 3.抗肿瘤抗生素：抗肿瘤抗生素通过抑制酶的作用和有丝分裂或改变细胞膜来干扰DNA。抗肿瘤抗生素为细胞周期非特异性药物，广泛用于对癌症的治疗。 4.植物类抗癌药：植物类抗癌药都是植物碱和天然产品，它们可以抑制有丝分裂或酶的作用，从而防止细胞再生必需的蛋白质合成。植物类抗癌药常与其它抗癌药合用于多种癌瘤的治疗。 5.激素：皮质类固醇激素用于治疗淋巴瘤、白血病和多发性骨髓瘤等癌症。当激素用于杀死癌细胞或减缓癌细胞生长时，可以把它们看成化疗药物。性激素用于减缓乳腺癌、前列腺癌和子宫膜癌的生长。它包括雌激素、抗雌激素、黄体酮和男性激素。性激素的作用方式不同于细胞毒素药物，属于特殊的化疗畴。 6.免疫制剂：免疫制剂可以刺激癌症病人的免疫系统更有效地识别和攻击癌细胞。它们属于特殊的化疗畴[1]。 化疗药物选择原则 首先，要根据病人的病理诊断和分期。不同病理细胞类型对化疗药的敏感性不同，不同的病理分期决定了不同的治疗目的，显然应选择不同的药物和剂量； 第二，根据肿瘤细胞的分裂周期，因为化疗药主要分成二类，一类叫细胞周期性特异性药物，一类叫细胞周期非特异性药物。这两类药具有各自不同的特点，把这两类药进行有机的组合，则作用的效果增强，能对不同周期时段的细胞起最大的杀伤效果； 第三，根据患者的身体情况选择化疗药物； 第四，在化疗药物中加入适当的化疗增敏药物和预防化疗副作用的药物，如止吐药、抗过敏药； 第五，化疗方案的选择同时需考虑病人的经济情况。 化疗药物的毒副作用 目前临床使用的抗肿瘤化学治疗药物均有不同程度的毒副作用，有些严重的毒副反应是限制药物剂量或使用的直接原因。它们在杀伤肿瘤细胞的同时，又杀伤正常组织的细胞，尤其是杀伤人体中生长发育旺盛的血液、淋巴组织细胞等。，而这些细胞与组织是人体重要的免疫防御系统，破坏了人体的免疫系统，癌症就可能迅速发展，造成严重后果。化疗的毒副反应分近期毒性反应和远期毒性反应两种。近期毒性反应又分为局部反应（如局部组织坏死、栓塞性静脉炎等）和全身性反应（包括消化道、造血系统、免疫系统、皮肤和粘膜反应、神经系统、肝功能损害、心脏反应、肺毒性反应、肾功能障碍及其他反应等）。远期毒性反应主要是生殖功能障碍及致癌作用、致畸作用等。此外，化疗由于其毒副作用，有时还可出现并发症，常见的有感染、出血、穿孔、尿酸结晶等。 常见的毒副作用有： （1）局部反应 一些刺激性较强的化疗药物当静脉注射时可引起严重的局部反应。 A.静脉炎：表现为所用静脉部位疼痛、发红，有时可见静脉栓塞和沿静脉皮肤色素沉着等。 B.局部组织坏死：当刺激性强的药物漏入皮下时可造成局部组织化学性炎症，红肿疼痛甚至组织坏死和溃疡，经久不愈。
大剂量顺铂化疗处理.doc
大剂量顺铂化疗处理 (总分 6,考试时间 600 分钟 ) 一、多项选择题 1. 大剂量顺铂化疗用药期间利尿措施采用下列哪些方法：（） A.多饮水 B.应用速尿 C.应用氨体舒通 D.应用甘露醇 E.大量输液 二、填空题 1.临床上对 ________ 、 ________ 、 ________、 ________ 、 ________ 的患者应慎用或不采用大剂量顺铂化疗。 2.大剂量顺铂化疗用药期间应给予________ 、 ________ 、 ________ 。 三、问答题 1.大剂量顺铂化疗的适应证和禁忌证。 2.试述大剂量顺铂化疗的操作要点。 3.试述大剂量顺铂化疗的注意事项。 1. B,D 2. 年龄大血管硬化肾功能差有听力障碍对化疗消化道反应缺乏耐受 3. 水化利尿措施补充电解质 4.实体瘤化疗中需要使用顺铂者均可采用大剂量顺铂化疗。但对年龄大、血管硬化、肾功能差 和有听力障碍及对化疗消化道反应缺乏耐受性的患者应慎用或不用大剂量顺铂化疗。 5.大剂量顺铂化疗的操作要点为： （1）顺铂溶于生理盐水或 3％氯化钠 200 ml 中静滴，并采用水化与甘露醇、呋塞米利尿的方法， 以减轻肾脏毒性。 （2）一般在应用大剂量DDP 之前先补液加 10％氯化钾20 ml 。 DDP 之后继续输液(生理盐水或 5 000 ml( 每 5％葡萄糖盐水注射液 1 000 ml 液体给氯化钾 )1 000 ～ 2 000 ml ， 20 mmol) 。输液从 DDP 给药之前12 小时开始，持续到DDP 滴完后24 小时为止。 （3）为促进利尿，输注DDP 之前先快速静滴20％甘露醇125 ml ， DDP 醇 125 ml 快速静滴，并根据尿量适当使用速尿。 之后再给予20％甘露（4）此疗法每 3 周一次，可重复3～4 次。 6. 大剂量顺铂化疗注意事项： （1）治疗中注意复查血清尿素氮、肌酐，有以下情况者禁用或停用本品：①早期肾脏毒性，如尿中白细胞10 个／高倍镜视野、红细胞或管型 5 个 /高倍镜视野以上者。② 血清肌酐超 过 186 ～351 mmol ／ L 者。③有肾脏疾患史、肾功能不良的病人。
化疗药物分类
化疗药物可杀灭肿瘤细胞。这些药物能作用在肿瘤细胞生长繁殖的不同环节上，抑制或杀死肿瘤细胞。化疗药物治疗是目前治疗肿瘤的主要手化疗药物，是对病原微生物、寄生虫、某些自身免疫性疾病、恶性肿瘤所致疾病的治疗药物。段之一 化疗药物分类 分类类别非专利名称疾病 烷化剂环磷酰胺 异环磷酰胺 烃化磺酸酯类白消安CML（慢性粒细胞白血病） 亚硝胺类卡莫司汀 三氮烯类达卡巴嗪恶性黑色素瘤、HD（霍奇金淋巴瘤）、 软组织肉瘤 替莫唑胺神经胶质瘤、恶性黑色素瘤 抗代谢类叶酸同类物甲氨蝶呤ALL（急性淋巴细胞白血病）、绒毛 膜癌、蕈样霉菌病、乳腺癌、头颈部 癌、肺癌、成骨肉瘤 培美曲塞肺癌、胸膜间皮瘤 嘧啶同类物氟尿嘧啶乳腺癌、结肠癌、胃癌、胰腺癌、卵 巢癌、头颈部癌、尿道膀胱癌 卡培他滨 阿糖胞苷AML（急性髓细胞白血病）、ALL 肺癌、胰腺癌、卵巢癌 吉西他滨（禁 冷藏） 巯嘌呤ALL、AML、CML 嘌呤同类物及 其抑制剂 硫鸟嘌呤ALL、AML、CML 喷司他丁毛细胞白血病、蕈样霉菌病、CLL（慢 性淋巴细胞白血病）、 克拉屈滨 氟达拉滨 天然产物长春碱类长春碱HD、乳腺癌、睾丸癌 长春新碱ALL、神经母细胞瘤、Wilms（肾胚 胎瘤）肿瘤、横纹肌瘤、HD、小细 胞肺癌 紫杉碱类紫杉醇卵巢癌、肺癌、乳腺癌、头颈部癌、 胃癌 多西他赛 表鬼臼毒素类足叶乙甙睾丸癌、小细胞肺癌、其他肺癌、乳 腺癌、HD、AML、Kaposi（多发性 特发性出血性）肉瘤 喜树碱类伊立替康卵巢癌、小细胞肺癌、结直肠癌 蒽环类抗生素放线菌素D 绒癌、肾母细胞瘤、横纹肌瘤、睾丸 癌、Kaposi肉瘤 多柔比星（阿软组织肉瘤、成骨肉瘤、HD、NHL、
常用化疗药分类
细胞处于对应时相才有效，故应慢滴。（文生氏公式）化疗药物给药剂量按体表面积计算2.21529 -0、128×体重（kg）cm=0、0061×身高（）+0m体表面积（、）2，做m1、660工作中计算体表面积：以身高1、6m，体重公斤，体表面积为调整5年，算治愈3.肿瘤病人治疗后，无复发，生存率≥联合化疗方案药物成原则4. 得药物组成a、两种以上作用机制不同药物配合非特异性药物与不同时相得周期特异性b、周期毒性不相重复c、各药得个药合用一般用于复发42-3个药合用，个药物最好,临床上一般4d、一般3～得肿瘤患者或者难治性得血液病患者，5、化疗药物得器官毒性（多柔比星，阿霉素）：心脏毒性ADR （博来霉素）：肺纤维化BLM 肾毒性DDP（顺铂）： 神经毒性PTX（紫杉醇）：L-OHP（奥沙利铂）、VCR（长春新碱）、 （卡莫司汀）：肝毒性BCNU 化疗分为6.又称新辅助化疗，实施局部治疗方法（如手术或放疗）前所做得:a、诱导化疗以利于后续得手目得就是使肿块缩小、及早杀灭瞧不见得转移细胞，全身化疗，术、放疗等治疗。对于早期与晚期肿瘤患者不采用新辅助化疗得方法。减少复发，杀灭手术无法清除得微小病灶，手术治疗与放疗得后，辅助化疗b、:提高生存率。． c、姑息化疗:对于手术后复发、转移或就诊时不能切除得肿瘤病人，目得并不就是彻底地消灭肿瘤，而在于能够平稳地控制肿瘤得进展，缓解患者得痛苦，延长其生命。这时得化疗称作“姑息化疗”。 7、常用细胞周期特异性药物 S期特异性药物：
抗叶酸类：甲氨蝶呤（MTX，胸腺嘧啶、嘌呤）、培美曲塞（PEM，胸腺 （嘧啶）雷替曲塞（胸腺嘧啶）、六甲蜜胺嘧啶、嘌呤，）、、前体药）希罗达，5-FU、卡培她滨（CAPE，5-FU抗嘧啶类：氟尿嘧啶（）吉美嘧啶+替吉奥（替加氟（FT207，5-FU衍生物）、替加氟抗代谢类，HCFU+尿嘧啶）、卡莫氟（+奥替拉西钾）、优福定（替加氟衍生物）、5-FU Ara-c)、）、吉西她滨(GEM，作用机制同阿糖胞苷（Ara-c Ara-c衍生物）安西她滨（巯嘌呤起作用）、（体内转化6-6-MP）、硫唑嘌呤6-抗嘌呤类：巯嘌呤（苷类似物，抗病毒类）、硫鸟嘌呤，阿糖腺氟达拉滨（Ara-A，新得抗代谢药，本品就是从链霉DCF）、6-TG 喷她司丁（（素菌中分离得得抗生素）(HU) ：羟基脲干扰嘌呤与嘧啶合成 、）（CPT-11（HCPT），伊立替康羟喜树碱拓扑异构酶I：喜树碱类，拓扑异构酶抑制剂拓扑替康 VM-26）依托泊苷（VP-16）、替尼泊苷（：拓扑异构酶II、）长春瑞滨（NVB长春新碱）、（VCR）、（M期特异性药物：长春碱类：长春碱VLB ）长春地辛（VDS DOC））、紫杉类：紫杉醇（PTX多西她赛（门冬酰胺酶），肾上腺皮质类固醇L-ASP（L-期特异性药物：G1成BLM（PYM，国内，与 BLM期特异性药物：G博来霉素（，国外）、平阳霉素2分相近）影响蛋白质功能与合成得药门冬酰胺酶、培门冬酶、高三尖杉酯碱． 8、细胞周期非特异性 DNA结构与功能）烷化剂（DNA交联剂，
大剂量化疗药物注意事项
大剂量化疗药物注意事项 顺铂化疗的水化和注意事项 临床研究已表明，大剂量顺铂 (PDD) 对多种实体肿瘤有效，常用于治疗头颈部癌、肺癌、食管癌、卵巢癌和宫颈癌等，疗程为每4 周一次，化疗的剂量是 80-120 mg/m2。大剂量顺铂化疗在无水、无利尿措施时肾毒性发生率为 100% 。 水化可缩短顺铂血浆浓度半衰期、增加顺铂肾脏清除率。水化可不改变顺铂血药浓度及尿液顺铂排泄量，同时降低尿中顺铂浓度，减少与肾小管细胞结合，从而减少顺铂肾脏毒性。 大剂量顺铂化疗的水化和利尿 用药前 12 小时持续到用药结束 24 小时，静脉滴注 20 ml 氯化钾 +1000 ml 生理盐水，滴速 5-6 ml/min。 用药，静脉滴注顺铂 + 生理盐水 200 ml，30-40 min 滴完。 用药后，快速静脉滴注 20% 甘露醇 250 ml，20-30 分钟内滴完；静脉滴注 40-60 ml 氯化钾 +2000-3000 ml 生理盐水，滴速200-300 ml/h。 日输液总量 4000-5000 ml（3000 ml/m2）。水化至少 3 天。 密切监测出入液量，以防输液过快增加心脏负担。尿量不足、体重增加提醒水潴留，可先予快速静脉滴注 20% 甘露醇 125 ml，再静推 20 mg 呋塞米脱水。 毒副反应
恶心呕吐：用药后 1-2 h 发生，可持续一周左右，停药后 2-3 天消失。用强效止吐剂如 5- 羟色胺 3、地塞米松、昂丹司琼等控制急性呕吐。 剂量限制性肾毒性：用药剂量 90 mg/m2 以上高危，常见于用药 10-15 天后发生。表现为血尿，血尿素氮升高、血肌酐升高，肌酐清除率降低，常为可逆性，但反复、大量治疗可致轻中度肾损害。除了充分水化外，尚无有效的方法处理。 神经毒性：与用药总剂量有关。表现听神经毒性如耳鸣、耳聋、听力下降，末梢神经毒性表现为手脚袜套样感觉减弱或丧失、肌力下降等，通常难以恢复。 骨髓抑制：发生率与剂量相关，剂量≤ 100 mg/m2，发生率10%-20%；剂量≥ 120 md/m2，约为 40%，可与联合化疗中其他抗癌药的骨髓毒性相累加。白细胞＜ 3.5x10^9/L 或血小板＜ 75x10^9/L 时停用。 甲氨蝶呤化疗的注意事项 小剂量 MTX 化疗疗效较差，甚至无效，易产生耐药性。 大剂量或超剂量甲氨蝶呤（MTX）化疗，血药浓度显著增高，可透过血脑屏障，甚至到达血运不佳的实体瘤。 然而，大剂量 MTX 化疗在增高细胞毒作用的同时，患者会出现严重的骨髓抑制、消化道反应、肾功能障碍等毒副作用。
大剂量卡铂化疗的药物毒性观察
大剂量卡铂化疗的药物毒性观察 高 和 纪树国 宋艳红 摘要 目的:探讨大剂量卡铂化疗的安全性。方法:对6例接受大剂量卡铂并自体骨髓移植(A BM T)治疗的肺 癌患者化疗期的药物毒性进行了观查。卡铂总剂量从560～1375mg/m2,按预定方案分次静滴。5例加用V P-16 300mg,1例并用M M C6mg和V C R2mg。结果:主要毒性反应为白细胞总数、中性粒细胞、血小板减少和脱发(W HO毒性反应Ⅲ～Ⅳ级)其次是贫血、皮肤粘膜出血、呕吐和可逆性肝功能损害。其中口腔粘膜溃疡及轻度发烧各2例,一过性蛋白尿、室上性心动过速和便秘各1例,尿素氮和肌酐未见升高;全部患者骨髓均获解救,从自体骨髓回输到骨髓造血功能重建成功平均26.67(17～32)d。结论:大剂量卡铂并ABM T治疗肺癌,在我们所使用的剂量范围内,患者是可以耐受的。 关键词 卡铂;药物毒性;骨髓移植;肺肿瘤 中国图书资料分类法分类号 R734.2 Study on the toxicity of high dose carboplatin chemotherapy G ao He,J i Shuguo,Song Yanhong(Air Force G eneral Hospital of PL A,Beijing 100036) Abstract Objective:T o inv estig ate the to xicity of the la rg e do se ca rbopla tin.Methods:6pa tients suffer ed fr om lung ca n-cer we re tr eated with high do se ca rbopla tin with auto lo go us bo ne mar ro w tr ansplantatio n.the tota l do ses o f car bo pla tin rang ed fr om560to1375mg/m2,a nd V P-16300mg in5pa tients a nd M M C6mg V CR2mg in1patient w er e added to th e regem ents.Results:The mainly tox ic r eactio ns w ere leuko penia、neutro penia、thr ombocy topenia and hair lo ss(W HO g ra deⅢ～Ⅳ)follo w ed by anemia、bleeding、v o mi ting and rev ersible h epato xicity.M uco us membr ane ulcera tio n and moderate fev er w ere o bserv ed in each2pa tients;there wer e pro teinuria、superior v ent ricula r tachy ca rdia a nd co nstipa-tion in each1patie nt;BU N a nd Cr w er e nor mal The bone ma rr ow o f all patie nts was rescued successfully,and the ev er-ag e time of r ecov e ry w as26.67(r ang e17to32)da ys fro m its reinfusio n to r eco nstructio n o f hemopo sitic func tio n. C onclusion:Tr ea ting lung cancer wi th hig h do se ca rboplantin with ABM T wa s safe in this do se range w e taked. Key words carbo platin;dr ug to xicity;bone mar ro w tra nsplanta tio n;lung neo plasms 卡铂是继顺铂之后的第二代铂类抗癌药,单药抗癌疗效高,其M TD为400～500mg/m2每4～6周1次,推荐用量200～300mg/m2。与顺铂相比卡铂主要的剂量限制性毒性是BM抑制,而BM外毒性较轻,是近年来国外研究推荐用于大剂量化疗的药物。我们选用国内济南齐鲁药厂生产的卡铂并自体骨髓移植(ABM T)治疗肺癌6例,现将其毒性反应观察结果报告如下。 1 材料和方法 1.1 对象 6例均为空军总医院呼吸内科住院肺癌患者,男性5例,女性1例。平均年龄41.8(19～55)岁;全部患者均经病理诊断。从发病到开始接受 作者单位 空军总医院呼吸科,北京 100036 ABM T时间平均8.3(3～14)个月,ABM T前经全面系统体检、临床检验、心电图、X片、CT、腹部B 超、超声心动图,核素骨扫描等项检查,进行评价。评价标准:一般状况按卡氏(Karnosky)计分法;临床分期,SCLC按1993年美国V A-SLG分型标准,非小细胞肺癌(N SCLC)按1988年IASLG修订TNM 分类。结果,小细胞肺癌(SCLC)5例,均为广泛型,低分化鳞癌1例T2N2M1,卡氏计分50分、60分、70和90分各1例,80分2例,全部患者AB TM前经多部位BM穿刺病理检查无BM转移,肝肾功能正常。 1.2 方法 1.2.1 ABM T前患者的临床准备和化疗期监测 为了确保这一治疗技术的顺利完成和准确全面评价
大剂量顺铂化疗水化及利尿的监护
大剂量顺铂化疗水化及利尿的监护 据文献报道大剂量顺铂治疗恶性肿瘤病人的有效率为40.3%,常规剂量治疗恶性肿瘤的有 效率为24.3%,说明大剂量顺铂治疗比小剂量顺铂的疗效为优.但由于剂量的增加,药物毒性加大,尤其是肾脏毒性发生率可达1oo%.为了提高顺铂的疗效.减少顺铂的肾脏毒性,我科采取水化及利尿措施进行大剂量顺铂化疗.现将我科20例患者使用大剂量顺铂化疗水化及利尿的监护报告如下. 1.临床资料 本组病例为 1998年10月～ 1999年10月在本科住院的晚期肿瘤患者,共20例,均经病理确诊. 其中男性10例.女性10例,年龄17～60岁,均经病理确诊.其中小细胞肺癌5例.食管癌6例,骨肉瘤2例,睾丸非精原细胞瘤1例.每例患者化疗至少2周期,4周为1周期. 2. 水化及利尿的方法 按照100mg/m2计算顺铂的用量.在大剂量顺铂给药前先给 5%GNs1000ml+10%KCL 10 ml静脉滴注.顺铂加入200mlNS中静脉滴注,在30～40min滴完.顺铂滴完后给20%甘露醇250静脉滴注,于20～30 min滴完,并给予大量补液以达到利尿作用,降低顺铂在肾小管中的积聚.一般化疗的第1天和第2天每日给液体总量为3000--4000ml,输液中根据尿量每次给予速尿20 mg静脉注射.第3天补液总量为2 000～3 000 ml. 3水化及利尿的监护 3.1做好治疗前病人状况的评估及心理护理:
用药前应充分了解患者的生理和心理状态.要求患者心,肝,肾功能正常,血常规,尿常规正常,Kamofskys'评分>70分,无糖尿病等其他合并症.1个月内未进行化疗.同时做好心理护理.向患者说明治疗的目的及意义,在用药期间可能存在的不适及注意事项,以调动患者的积极因素,树立与疾病作斗争的信心和勇气,使患者能够主动配合完成治疗. 3.2水化治疗的监护: (1)保证按时准确地执行每日进入的总液体量. (2)选择合适的静脉,保持静脉通畅.在用药过程中.除加强巡视及密切观察局部外,还应使患者保持舒适的体位,告诫患者如何保护好穿刺部位,需要大小便时,一定要有护士协助. (3)一旦不慎将药物漏人皮下.应立即停止注药.若为顺铂漏人皮下,局部用1%普鲁卡因5 ml+Ns 5ml+DXM 5 mg行环行封闭及0.1%洗必泰湿敷24 h.同时抬高患肢,更换穿刺部位,确保每天的液体于12 h左右输完. (4)观察患者是否有心慌,朐闷,呼吸困难等症状.以防心力衰竭,肺水肿或水中毒等并发症的发生;对出汗多,呕吐较严重者,酌情调整补液量,合理应用止吐药物,同时鼓励病人多饮水. 3.3利尿的监护: (1)准确记录24h出入量: 保证24h尿量不少于3000m1.连续记录3d.尤其在用药的前4 h之内尿量不能少于100ml/h,若前4 h每小时尿量不足应随时调整液速.对入量已足,尿量仍少者,应及时向医生回报.应用利尿药 (2)观察尿液的颜色及性质: 若患者尿液色深而浑浊.且呈酸性.应立即通知医生,以防急性肾功能衰竭的发生. (3)预防院内感染:
常用的化疗药物使用方法以及副作用
紫杉醇，培美曲塞，多西他赛，顺铂，卡铂，伊立替康，贝伐珠单抗，奥沙利铂，多柔比星，表柔比星，新碱，环磷酰胺，氟尿嘧啶，吉西他滨，阿糖胞苷，曲妥珠单抗，利妥昔单抗，卡培他滨，替吉奥。 1、紫杉醇 用法:静滴，滴注本药时应采用非聚乙烯材料的输液用具，治疗前按常规应用地塞米松和H2受体拮抗剂进行预处理。 滴注时间: 3小时 副作用: a过敏反应、末梢神经障碍、肌肉酸痛、关节痛、心脏毒性(特有的) b骨髓移植 c脱发 d恶心呕吐 2、培美曲塞 用法用量:静滴，本品联合顺铂时应在本品给要结束30min后再给予顺铂滴注，用0.9%氯化钠注射液稀释至100ml,静滴超过10min 保存：室温保存，配置好的溶液，置于冰箱冷藏或置于室温( 15-30C)无需避光，其物理及化学特性24小时保持稳定。 副作用:白细胞减少，中性细胞减少，发热，乏力，皮疹，腹痛，肝肾功能异常。 护理要点: A接受本药治疗同时接受叶酸和维生素B12的补充治疗，减少血液学和胃肠道的反应，第一次给予本药治疗开始5-7 天服用叶酸，-直服用整个治疗周期，在最后一次本品给药后21天可停服。患者还需在第一次本品给药前7天肌注维生素B12一次，以后每三个周期肌注一次，以后的维生素B12给药可与本品用药在同一天进行。 B本品与吉西他滨合用时，应在使用吉西他滨90min 后再使用本药。 C预服地塞米松可以降低皮肤反应的发生率及严重程度。 3、多西他赛 用法:静滴，治疗前一-天服用地米，持续至少三天，防止过敏和体液潴留。 滴注时间:1小时。 副作用: A骨髓抑制；
B过敏反应； C皮肤反应:红斑，皮疹； D体液潴留:水肿； E胃肠道反应； F本要外周用药后1周可出现延迟性静脉炎或局部皮肤反应； G肝功能损害。 4、顺铂 用法:静滴，胸腹腔注射，动脉注射。 保存:避光冷藏。 副作用: a胃肠道反应:严重的恶心呕吐，可持续一周； B骨髓抑制； c脱发； D肾损害，听力损害，神经损害，为减轻肾脏负担，需在给药前2-16h 和给药后6h大量补液，注意询问有无耳鸣； E不能接触含铝器具，会产生黑色沉淀及气体； F变态反应症状，溶血性贫血。 5、卡铂 用法:静滴，用5%葡萄糖溶解本品。 保存:室温避光保存，因制剂中无抗菌成分，按规定稀释后的药液，在室温中保持8小时稳定。 副作用: a特有的副作用:延迟性呕吐； B骨髓抑制； C脱发； D肾损害较轻，听力损害，神经损害，肝损害少见。 6、伊立替康 用法:静脉滴注30-90min，每三周一次。 保存:遮光，密闭保存。
化疗药物给药顺序原则精编WORD版
化疗药物给药顺序原则精编W O R D版 IBM system office room 【A0816H-A0912AAAHH-GX8Q8-GNTHHJ8】
化疗药物使用原则1、给药顺序基本原则 （1）药物相互作用原则 有的化疗药物之间会发生相互作用，从而改变药物的体内过程，可能影响疗效或毒性。如顺铂影响紫杉醇的清除率，先用紫杉醇再用顺铂。 （2）刺激性原则 使用非顺序依赖性化疗药物时，应先用对组织刺激性较强的药物，后用刺激性小的药物。由于治疗开始时静脉尚未损伤，结构稳定性好，药业渗出机会少，药物对静脉引起的不良反应较小如长春瑞滨和顺铂合用时，长春瑞滨刺激性强，宜先给药。 （3）细胞动力学原则 生长较慢的实体瘤处于增殖期的细胞较少，G0期细胞较多，先用周期非特异性药物杀灭一部分肿瘤细胞，使肿瘤细胞进入增殖期再用周期特异性药物。顺铂和依托泊苷合用时，先用顺铂后用VP-16。 化疗方案联用 药物 用药顺 序 原因 GP 吉西 他滨先用吉 西他滨 顺铂会影响吉西他滨的体内过程，加重 骨髓抑制。
生长快的肿 瘤先用周期特异性 药物大量杀灭处于 增殖周期的细胞， 减少肿瘤负荷，随 后用周期非特异性 药物杀灭残存的肿 瘤细胞。 用药顺序 2、联用顺铂化疗 PP方案：治疗无法手术的恶性胸膜间皮瘤及肺癌，尤其是腺癌。 3、联合长春新碱（VCR）化疗 化疗方 案联用药 物 用药顺序原因 CHOP 环磷酰 胺CTX 先用VCR，6-8小时 后在给CTX VCR具有同步化作用，使细胞停 滞在M期，约6~8h后细胞同步 进入G1期，再用CTX可增效。 VCM 甲氨蝶 呤先用VCR VCR阻止甲氨蝶呤从细胞内渗出 而提高细胞内浓度。 TP 紫杉 醇先用紫 杉醇 顺铂对细胞色素P450酶有调节作用，可 使紫杉醇清除率大约降低33%,产生更为 严重的骨髓抑制。 FP 氟尿 嘧啶先用顺 铂 小剂量顺铂能够增加细胞内蛋氨酸,使细 胞内活性叶酸生成增加,从而增加5-FU 的抗肿瘤作用。 PP 培美 曲塞先用培 美曲塞 若先用顺铂，随着肾功能的降低，培美 曲塞的血浆清除率降低，而全身暴露剂 量增加。
化疗药物常见分类之欧阳家百创编
化疗药物种类 欧阳家百（2021.03.07） 1.烷化剂：烷化剂直接作用于DNA上，避免癌细胞再生。此类药物对慢性白血病、恶性淋巴瘤、何杰金氏病、多发性骨髓瘤、肺癌、乳腺癌和卵巢癌具有疗效。 2.抗代谢药：抗代谢药干扰DNA和RNA的合成，用于治疗慢性白血病、乳腺癌、卵巢癌、胃癌和结直肠癌。 3.抗肿瘤抗生素：抗肿瘤抗生素通过抑制酶的作用和有丝割裂或修改细胞膜来干扰DNA。抗肿瘤抗生素为细胞周期非特异性药物，广泛用于对癌症的治疗。 4.植物类抗癌药：植物类抗癌药都是植物碱和天然产品，它们可以抑制有丝割裂或酶的作用，从而避免细胞再生必须的卵白质合成。植物类抗癌药常与其它抗癌药合用于多种癌瘤的治疗。 5.激素：皮质类固醇激素用于治疗淋巴瘤、白血病和多发性骨髓瘤等癌症。当激素用于杀死癌细胞或减缓癌细胞生长时，可以把它们看成化疗药物。性激素用于减缓乳腺癌、前列腺癌和子宫内膜癌的生长。它包含雌激素、抗雌激素、黄体酮和男性激素。性激素的作用方法不合于细胞毒素药物，属于特殊的化疗规模。 6.免疫制剂：免疫制剂可以安慰癌症病人的免疫系统更有效地识别和攻击癌细胞。它们属于特殊的化疗规模[1]。 化疗药物选择原则 首先，要根据病人的病理诊断和分期。不合病理细胞类型对化疗药
的敏感性不合，不合的病理分期决定了不合的治疗目的，显然应选择不合的药物和剂量； 第二，根据肿瘤细胞的割裂周期，因为化疗药主要分红二类，一类叫细胞周期性特异性药物，一类叫细胞周期非特异性药物。这两类药具有各自不合的特点，把这两类药进行有机的组合，则作用的效果增强，能对不合周期时段的细胞起最年夜的杀伤效果； 第三，根据患者的身体情况选择化疗药物； 第四，在化疗药物中加入适当的化疗增敏药物和预防化疗反作用的药物，如止吐药、抗过敏药； 第五，化疗计划的选择同时需考虑病人的经济情况。 化疗药物的毒反作用 目前临床使用的抗肿瘤化学治疗药物均有不合水平的毒反作用，有些严重的毒副反响是限制药物剂量或使用的直接原因。它们在杀伤肿瘤细胞的同时，又杀伤正常组织的细胞，尤其是杀伤人体中生长发育旺盛的血液、淋巴组织细胞等。，而这些细胞与组织是人体重要的免疫进攻系统，破坏了人体的免疫系统，癌症就可能迅速成长，造成严重后果。化疗的毒副反响分近期毒性反响和远期毒性反响两种。近期毒性反响又分为局部反响（如局部组织坏死、栓塞性静脉炎等）和全身性反响（包含消化道、造血系统、免疫系统、皮肤和粘膜反响、神经系统、肝功能损害、心脏反响、肺毒性反响、肾功能障碍及其他反响等）。远期毒性反响主要是生殖功能障碍及致癌作用、致畸作用等。另外，化疗由于其毒反作用，有时还可呈现并发症，罕见的有感染、出血、穿孔、尿酸结晶等。