1、實體癌化療基本知識梅蔚德2021/7/15 星期四1 1.合理化療的基本原理和要點2021/7/15 星期四21.1 化學治療的基本原理1.1.1 化療作用點 2021/7/15 星期四31.1.2 細胞周期與化療藥物1.1.2.12021/7/15 星期四41.1.2.22021/7/15 星期四51.1.2.32021/7/15 星期四61.1.3癌的增殖2021/7/15 星期四71.1.4腫瘤的生長比例和化療1.1.4.12021/7/15 星期四81.1.4.22021/7/15 星期四91.1.5細胞毒藥物對腫瘤的殺滅1.1.5.1對數殺滅 2021/7/15 星期四101.1.5

2、.2 劑量密度 2021/7/15 星期四111.1.5.3 生長比例改變 2021/7/15 星期四121.2化學治療無效或復發的有關問題1.2.1 “個體化問題”1.2.1.1 ERCC-1 (核苷酸切除修復交叉互補 組-1),主要在核內，低表達則伴隨基因不 穩定，產生惡性表型。2021/7/15 星期四1351例NSCLC手術標本 50 （低）35.594.6 50 （高）生存期（周）ERCC1表達P=0.012021/7/15 星期四14ERCC1高水平，鉑相對耐藥，低水平者鉑相對敏感。這對新輔助治療可能較為重要，33例鉑類新輔助治療結果ERCC1水平RRMST陽性31.3%36月陰性

3、58.8%54月 上述對宮頸癌，卵巢癌亦適用2021/7/15 星期四151.2.1.2 RRM1為核糖核苷酸還原酶亞單位M1，主要在核內，功能為將核苷酸還原為脫氧核苷酸，在NSCLC治療中，高水平對健擇及鉑耐藥。 1.2.1.3 T S 為胸甘酸合酶，核及胞漿內均有，高水平時對5-FU及培美曲塞耐藥2021/7/15 星期四161.2.1.4 BRCA1（乳癌-1基因），為乳癌，卵巢癌易感基因，涉及DNA損傷修復，低水平者（0.61）生存期長于高水平者（2.45）p=0.01,對鉑敏感。突變的BRCA1（編碼第1815個氨基酸的密碼子中G突變為A）對紫杉醇敏感。2021/7/15 星期四17

4、1.2.2 耐藥及其解決方法 1.2.2.1 細胞動力學因素（生長比例小）可采取手術/放療 降低腫瘤體積應用可殺休止期細胞的藥物 用藥安排中應防止對某時相的忽略促成時相同步化2021/7/15 星期四181.2.2.2 生物化學因素包括影響藥物吸收，藥物激活障礙，藥物進靶細胞少而排除多，損傷DNA的快速復原，誘導癌凋亡受阻，MDR蛋白出現等，其中，相當一部分與基因突變有關，（如p53，HER-2，K-ras等）對策： 聯合化療，G-CSF支持下或造血干細胞移植條件下大劑量化療，鈣通道阻滯劑，抗心律失常藥，環孢菌素D, 在某種情況下化療與靶向治療同用，如Cetuximab可逆轉CPT-11對大腸

5、癌的耐藥性。2021/7/15 星期四191.2.2.3 癌干細胞1.2.2.3.1 致癌干細胞在癌瘤中的重要性 to share characterists with healthy stem cells (self renew, multilineage differentiation, and maintained proliferationactivation of survival responses, promotion of vessel formation, enhanced motility)2021/7/15 星期四20 Recapitulate tumorigenesis

6、 when xenotransptanted To contribute to therapeutic resistance, so eradication of the stem-cell compartment of a tumor may be essential to achieve stable, long-lasting remission, and even cure of cancer 2021/7/15 星期四21From CraigT.Jordan et al2021/7/15 星期四221.2.2.3.2 近代研究證實致癌干細胞(腫瘤起始細胞)的存在 The identi

7、fication of tumorinitiating cells Hemotopoietic system 血液系統：CD34-CD38+ Lapiodot T et al:(Genes Dev.2003 Dec 15; 17C24 3029-35)To identify an human AML-initiating cell (AIC) by transplatation into SCID mice, these cells homed to BM, resulting a pattern of dissemination, and leukaemic cell morphology

8、similar to that seen in original patient AIC in the blood of AML patients was one engraftment unit in 250,000 cells2021/7/15 星期四231.2.2.3.3 乳癌“干細胞” (From Muhammad AI-Hajj, Proc Natl Aca 5c; USA 2003:100:3983-88) CD44+CD24- / low Lineage- 1.2.2.3.4 腦腫瘤“干細胞 ” CD133+ (prominin 1) 1.2.2.3.5 結腸癌“干細胞” CD1

9、33+1.2.2.3.6 胰腺癌“干細胞 ” CD44, CD24, and epithelial-specific antigen(ESA)均陽性。1.2.2.3.7 進一步的明確干細胞可以由此研究出針對其 特性的殺滅藥2021/7/15 星期四242 化療指征及方案2.1 由循證醫學決定(NCCN)，目的在于盡可能保證“量體裁衣”,既不治療過度又不治療不足，其依據主要為：2021/7/15 星期四252.1.1 關于NCCN(國立綜合癌癥網)（1） a not-for-profit alliance of 21 of the worlds leading cancer centers為21

10、個世界首要癌癥中心的非盈利性聯盟組織 （2）The leadership and expertise of clinical professionals at NCCN Member Institutions 臨床專家組成的委員會 （3）The primary goal of all NCCN initiatives is: improving the quality, effectiveness, and efficiency of oncology practice so patients can live better lives 主要任務：不斷改進患者生活質量，治療效果及效率-改善生存

11、2021/7/15 星期四26（4） The development of NCCN information is based upon the independent evaluation of available scientific evidence integrated with the expert judgment of leading clinicians. 由首要的臨床專家們對提供的科學證據進行獨立評估并結合專業判斷，據此每年改進NCCN“指南” 2.1.2 Clinical Trials 指南內容根據-臨床試驗結果 （1） The NCCN believes that the

12、 best management for any cancer. Patient is in a clinical trial. Participation in clinical trials is especially encouraged.2021/7/15 星期四27（2） All recommendations are Category 2A unless otherwise specified（3） NCCN Categories of Evidence and Consensus: NCCN 臨床證據及評判意見一致性的分類 如下表2021/7/15 星期四28Category o

13、f Evidence and Consensus臨床證據及小組評判分類Quality of Evidence證據的可靠性 Level of Consensus評價的一致性1High: high-powered randomized clinical trials or meta-analyses Uniform: near unanimous positive support with some possible neutral positions 2ALower: Lower level evidence is interpreted broadly, and runs the gamut

14、from phase or large cohort studies to individual practitioner experience. In many instances, the retrospective studies are derived from clinical experience of treating large numbers of patients at a member institution, so panel members have first-hand knowledge of the data Uniform 2BLowerNon-uniform

15、3AnyMajor disagreement2021/7/15 星期四292.1.3 Safeguards for Eliminating Biases 消除指南偏差 2.1.3.1 Two safeguards listed as follow: panels reflecting all schools of thought for a particular tumor, and the process of iteration and feedback 廣泛性及反復討論 2.1.3.2 To address bias is the presentation of new NCCN Gui

16、delines at the annual meeting, where meeting attendees are invited to provide both oral and written comments on the guidelines.每年年會根據臨床試驗的結果，討論對指南的不同意見形成新指南 2021/7/15 星期四302.1.4 指南形成過程 NCCN Guidelines Development Process“指南”指導委員會挑選主要內容 Guidelines Steering Committee Selects Topic 某指南專門小組 Guideline Pa

17、nel Selected 形成某指南一稿 Preliminary Pathway Derivation 多中心復核 小組材料討論按NCCN方法當歸納 Institutional Review Collection 采集補充 Guideline Revision 指南修正 Final Guideline 指南定稿 Continuous Review 繼續復核2021/7/15 星期四312.1.5 NCCN 開本格式Treatment Pathways 治療步驟 診斷Diagnosis 檢查分期Work-up&Staging首要初治Primary Treatment 輔助治療Adjuvant T

18、herapy復發治療、補救治療Salvage/Recurrence Therapy 對癥、支持處理步驟Symptom Management/ Supportive Care Pathways篩查Screening危險性評估RiskAssessment分級Triage特異性評估SpecializedEvaluation特異性干預SpecificIntervention再次評估Reevaluation隨訪Follow-up2021/7/15 星期四322.1.2 病理診斷是關鍵，除組織形態學外，還常需分子病理學（分子遺傳病理，免疫組化病理）嚴格重視病理診斷應與臨床診斷一致。存在下列兩種情況，可在無

19、病理診斷下行治療（約1%）。a 建立診斷的措施或不迅速治療將導致較嚴重后果或死亡b 良性病變可能性小2021/7/15 星期四332.1.3 在TNM分類的基礎上分期（以胃癌為例2009）2.1.3.1 2021/7/15 星期四342.1.3.22021/7/15 星期四352.1.3.32021/7/15 星期四362.1.3.42021/7/15 星期四372.1.4 體能狀態分級 2021/7/15 星期四382.2 應用化療的四種目的2.2.1 Adjuvant chemotherapy 輔助性化療 （根治性手術/放療后）2.2.1 Primary/Neuadjuvant chemo

20、therapy:起始/新輔助化療（局部根治性手術/放療前，少數疾病作為主要治療）2.2.3 局部治療（如介入，腔內應用等）2.2.4 晚期疾病的姑息治療2021/7/15 星期四392.3 化療毒副反應及其處理2.3.1 推薦WHO或美國NCI的不良反應分類，分1，2，3，4度，1，2度為可允許反應，3度應避免，發生后應停藥，日后需再行化療要改善調整劑量，4度則需立即停藥，急救及時，慎重處理。2021/7/15 星期四402.3.2 通過用藥方式削弱蒽環類的毒性并提高療效。 2021/7/15 星期四412.3.3 抗惡心嘔吐處理原則 抗5HT3 受體拮抗劑（如樞復寧類）最可靠，無禁忌下應與地

21、塞米松合用，以化療前0.5-1小時開始用最佳，化療結束后再用1-3日，主要針對急性嘔吐。 Aprepitant(抗敏吐/阿瑞匹坦)，為神經激肽-1受體拮抗劑，對急性，特別是延遲性嘔吐均有效，可與上方案聯合應用。 未用化療前的“預期性嘔吐”，常有心理因素，可予心理治療及治療前一日用Lorazepan(羅拉)0.5mg-2mg每4-6小時一次。（可有遺忘，精神錯亂等副作用）。或安定10mg化療前2小時肌注或靜注 2021/7/15 星期四422.4 時辰化療 以下摘自Michcel perry: The chemotherapy sorce book (2nd Edition）2.4.1 時辰影響

22、水平：生理和病理，系統和器官，細胞和分子2.4.2 時辰化療的需要：不少非時辰化療方案對平衡宿主腫瘤損害，毒性和治療指數有欠缺。2.4.3 抗癌治療時辰依賴性的基礎2021/7/15 星期四432.4.3.1 時辰性藥理動力學：吸收，分布，代謝，排泄2021/7/15 星期四442.4.3.1.12021/7/15 星期四452.4.3.1.22021/7/15 星期四462.4.3.2機體組織細胞動力學：S時相特異性藥物對胃腸道及骨髓損害以夜間給藥為輕。2.4.3.3 內分泌及免疫：腎上腺皮質激素，T，B，NK細胞及各種免疫反應。2.4.3.4 癌瘤時辰特點2021/7/15 星期四472.

23、4.3.4.1 2021/7/15 星期四482.4.3.4.2 癌瘤血流時辰性，實驗表明皮下癌瘤活躍時相與非活躍時相供血相差一倍，但不伴瘤體積變化，此時給藥化療療效增強。2.4.3.4.3 時辰治療對療效與毒性的影響2021/7/15 星期四492.4.3.4.3.12021/7/15 星期四502.4.3.4.3.2 2021/7/15 星期四512.4.3.4.3.32021/7/15 星期四522.5 如何預防繼發癌2.5.1 Define the risk of recurrence and tailor the intensity of cancer therapy: Loweri

24、ng the dose of treatment for low risk groups is probably the important way to prevent secondary cancer 2021/7/15 星期四532.5.2 Avoid radiation therapy2.5.2.1 This has been successful in childhood ALL where intrathecal chemotherapy has been substituted for radiation2.5.2.2 Hodgkins disease and non-Hodgk

25、ins lymphoma:where certain groups of patients have been found to survive just as well with chemotherapy alone as with chemotherapy plus radiation therapy2021/7/15 星期四542.5.3 Avoid drugs with high carcinogenic potential2.5.3.1 This is difficult to do since all chemotherapy drugs are carcinogenic 2.5.

26、3.2 Etoposide is associated with a relatively high incidence of myelodysplasia and acute myeloid leukemia and in some instances other drugs could be used instead2021/7/15 星期四552.6化/放療心血管并發癥2.6.1 Edward T.H. etc; Cardiovascular complications of Cancer Therapy Diagonsis, Pathogenesis, and Management (

27、Circulation. 2004; 109 : 3112- 3131.)2021/7/15 星期四562.6.1.1 Cardiotoxic Syndromes Associated With Chemotherapeutic Agents（1） Agents associated with myocardial depression Anthracyclines Mitoxantrone(Novantrone) Cyclophosphamide(Cytoxan)high dose Trastuzumab(Herceptin) Ifosfamide(Ifex) All-trans retin

28、oic acid(Tretinoin)2021/7/15 星期四57（2） Agents associated with ischemia 5-FU (adrucil) Cisplatin (platinol) Capecitabine (Xeloda ) IL-22021/7/15 星期四58（3） Agents associated with hypotension Etoposide(Vepesid) Paclitaxel(Taxol) Alemtuzumab (Campath) 阿侖單抗 抗CD52 Cetuximab (Erbitux) 愛必妥抗表皮生長因子受體（HER1) Ritu

29、ximab (Rituxan) 美羅華 抗CD20 IL-2 Denileukin(Ontak) IL-2/白喉毒素融合蛋白 Interferon- All-trans retinoic acid(tretinoin) Homoharringtonine 高三尖杉酯堿（4） Agents associated with hypertension Bevacizumab(Avastin) 抗VEGF Cisplatinin(Platinol)2021/7/15 星期四59（5）Agents associated with other toxic effects Cardiac tamponade

30、 or endomyocardial fibrosis : busulfan(Myleran) Hemorrhagic myocarditil : cyclophosphamide(Cytoxan) Bradyarrhythmias: paclitaxel(Taxol),thalidomide(Thalomid) Raynaud phenomenon: vinblastine(Velban) Autonomic neuropathy: vincristine(Oncovin) QT prolongation or torsades de Pointes : arsenic trioxide(T

31、risenox) Pulmonary fibrosis : bleomycin(Blenoxane)2021/7/15 星期四602.6.2 Risk Factor for Developing Cardiovascular Complications2.6.2.1 Some chemotheraperapeutic agents evoke cardiotoxicity only when the drug is administered at high dose :examples include CHF and pericarditis with platinum drugs.Systo

32、lic dysfunction and pericarditis with cyclophosphamide.LV dysfunction with anthracyclines2021/7/15 星期四612.6.2.2Administering anthracyclines by continuous infusion over 24 to 92 hours rather than by rapid intravenous infusion could reduce the cardiotoxicity of these drugs.Busulfan causes tachyarrythm

33、ias, hypertension or hypotension, and LV dysfunction when injected but not when taken orally .2021/7/15 星期四62The combination of IL-2 and interferon significantly increases hypotension, but delivering interferon alone for the first 2 weeks followed by IL-2 has much less cardiovascular toxicity .(inte

34、rval )The combination of paclitaxel and doxorubicin caused CHF in 20% of cases if the interval between doxorubicin and paclitaxel was 15 to 30 minutes, but increasing the interval to 4 to 16 hours reduced the cardiotoxicity of this combination.2021/7/15 星期四632.6.2.3Advanced age is a known risk facto

35、r for anthracycline cardiotoxicity Cardiovascular side effects from a particular drug occur in a specific subset of cancer patients Cardiovascular complication from cisplatin only in patients with metastatic testicular cancer Episodes of cardiotoxicity from low-dose ifosfmide being more commom in pa

36、tients with lymphoma. Alemtuzumab being associated with LV dysfunction in patients with mycosis fungoides.2021/7/15 星期四642.6.3 cardiotoxicity Associated With Radiation Therapy2.6.3.1 Radiation-induced heart disease is higher in patients given high doses of radiation therapy concurrent with doxorubic

37、in.2.6.3.2 Vascular injury from radiation therapy can be silent; approximately 50% of asymptomatic patients develop new myocardial perfusion defects.2021/7/15 星期四652.6.3.3 Sudden death in patients is thought to result from diffuse intimal hyperplasis of all cornary arteries or from significant left

38、main stenosis. The mean interval for developing CAD (coronary artery disease ) after radiation therapy is approximately 82 months.2021/7/15 星期四662.6.3.4 Radiation therapy also causes fibrous thickening of the pericardium, ranging from 2 to 145 months. Pericardial effusion is typically an early prese

39、ntation. Whereas pericardial constriction is a late manifestation. Usually appearing after months.2.6.3.5 Myocardial fibrosis is also a side effect of radiation therapy . radiation also causes fibrous thickening of cardiac valves lefi-side valves are more often involved than right valves.2021/7/15 星

40、期四672.7預防與處理2.7.1 Monitoring Cardiovascular Toxiciity2.7.1.1 B-type natriuretic peptide (BNP) (B型利鈉肽 腦鈉素） has been shown to be elevated before the development of LV dysfunction.2021/7/15 星期四682.7.1.2 Provocative testing with exercise or dobutamine echocardiography may be sensitive for the early dete

41、ction of subclincial cardiomvonpathy and may provide an opportunity for therapeutic intervention before the development of overt LV dysfunction.2021/7/15 星期四692.7.1.3 Diastolic dysfunction is an early sign.2.7.1.4 Fractional shortening and LV ejection fraction are not sensitive for the early detecti

42、on of preclinical cardiac diaease.2021/7/15 星期四702.7.2 Strategies to Reduce Cardiovascular Toxicity and Manage Complications2.7.2.1Anthracycline toxicity can be minimized by reducing the total dose to A期均行輔助化療，R1R2者同樣是再切除/放化療后化療。2021/7/15 星期四873.5.2 新輔助化療3.5.2.1 胸壁，近端氣道或縱隔T3T4,N0-1 ,肺上溝瘤：可能切除者，行術前同步

43、放化療，（不能切除行常規同步放化療）。3.5.2.2 B(T3N0),A,B(T3-4,N1),可切除者術前同步放化療，（不能切除者常規同步放化療）3.5.2.3 推薦化療方案 （ NCCN 2009）2021/7/15 星期四882021/7/15 星期四892021/7/15 星期四903.6 乳癌3.6.1 可行新輔助化療者為：（一般3-4周期，無效換方案）3.6.1.1 要求保乳并且符合保乳手術條件者A(T2N0M0),B T2N1M0 T3N0M0 A(T3N1M0)3.6.1.2 A T0-3,N2,M0 B T4,N0-1,M0 C Tany,N3,M02021/7/15 星期四913.6.1.3 炎性乳癌 3.6.2 輔助治療：只要有下列條件之一，均可考慮 T 0.6-1cm (有不佳因素)，C1 T1cm N+2021/7/15 星期四923.6.3 對妊娠患者，乳房切除后有化療指征者或需保乳者，新輔助化療應在中1/3妊娠期開始。3.6.4 推薦化療方案 2021/7/15 星期四933.6.4.12021/7/15 星期四943.6.4.22021/7/15 星期四953.7卵巢上皮癌和輸卵管癌除A B高分化可觀察外，A