1、實(shí)體癌化療基本知識(shí)梅蔚德 1.合理化療的基本原理和要點(diǎn)1.1 化學(xué)治療的基本原理1.1.1 化療作用點(diǎn) 1.1.2 細(xì)胞周期與化療藥物1.1.2.11.1.2.21.1.2.31.1.3癌的增殖1.1.4腫瘤的生長(zhǎng)比例和化療1.1.4.11.1.4.21.1.5細(xì)胞毒藥物對(duì)腫瘤的殺滅1.1.5.1對(duì)數(shù)殺滅 1.1.5.2 劑量密度 1.1.5.3 生長(zhǎng)比例改變 1.2化學(xué)治療無(wú)效或復(fù)發(fā)的有關(guān)問(wèn)題1.2.1 “個(gè)體化問(wèn)題”1.2.1.1 ERCC-1 (核苷酸切除修復(fù)交叉互補(bǔ) 組-1),主要在核內(nèi)，低表達(dá)則伴隨基因不 穩(wěn)定，產(chǎn)生惡性表型。51例NSCLC手術(shù)標(biāo)本 50 （低）35.594.6 5

2、0 （高）生存期（周）ERCC1表達(dá)P=0.01ERCC1高水平，鉑相對(duì)耐藥，低水平者鉑相對(duì)敏感。這對(duì)新輔助治療可能較為重要，33例鉑類(lèi)新輔助治療結(jié)果ERCC1水平RRMST陽(yáng)性31.3%36月陰性58.8%54月 上述對(duì)宮頸癌，卵巢癌亦適用1.2.1.2 RRM1為核糖核苷酸還原酶亞單位M1，主要在核內(nèi)，功能為將核苷酸還原為脫氧核苷酸，在NSCLC治療中，高水平對(duì)健擇及鉑耐藥。 1.2.1.3 T S 為胸甘酸合酶，核及胞漿內(nèi)均有，高水平時(shí)對(duì)5-FU及培美曲塞耐藥1.2.1.4 BRCA1（乳癌-1基因），為乳癌，卵巢癌易感基因，涉及DNA損傷修復(fù)，低水平者（0.61）生存期長(zhǎng)于高水平者（2

3、.45）p=0.01,對(duì)鉑敏感。突變的BRCA1（編碼第1815個(gè)氨基酸的密碼子中G突變?yōu)锳）對(duì)紫杉醇敏感。1.2.2 耐藥及其解決方法 1.2.2.1 細(xì)胞動(dòng)力學(xué)因素（生長(zhǎng)比例小）可采取手術(shù)/放療 降低腫瘤體積應(yīng)用可殺休止期細(xì)胞的藥物 用藥安排中應(yīng)防止對(duì)某時(shí)相的忽略促成時(shí)相同步化1.2.2.2 生物化學(xué)因素包括影響藥物吸收，藥物激活障礙，藥物進(jìn)靶細(xì)胞少而排除多，損傷DNA的快速?gòu)?fù)原，誘導(dǎo)癌凋亡受阻，MDR蛋白出現(xiàn)等，其中，相當(dāng)一部分與基因突變有關(guān)，（如p53，HER-2，K-ras等）對(duì)策： 聯(lián)合化療，G-CSF支持下或造血干細(xì)胞移植條件下大劑量化療，鈣通道阻滯劑，抗心律失常藥，環(huán)孢菌素D,

4、 在某種情況下化療與靶向治療同用，如Cetuximab可逆轉(zhuǎn)CPT-11對(duì)大腸癌的耐藥性。1.2.2.3 癌干細(xì)胞1.2.2.3.1 致癌干細(xì)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) Recapitulate tumo

5、rigenesis 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 From CraigT.Jordan et al1.2.2.3.2 近代研究證實(shí)致癌干細(xì)胞(腫瘤起始細(xì)胞)的存在 The identification of tumorinit

6、iating cells Hemotopoietic system 血液系統(tǒng)：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 similar to that seen

7、in original patient AIC in the blood of AML patients was one engraftment unit in 250,000 cells1.2.2.3.3 乳癌“干細(xì)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(xì)胞 ” CD133+ (prominin 1) 1.2.2.3.5 結(jié)腸癌“干細(xì)胞” CD133+1.2.2.3.6 胰腺癌“干細(xì)胞 ” CD44, CD24, a

8、nd epithelial-specific antigen(ESA)均陽(yáng)性。1.2.2.3.7 進(jìn)一步的明確干細(xì)胞可以由此研究出針對(duì)其 特性的殺滅藥2 化療指征及方案2.1 由循證醫(yī)學(xué)決定(NCCN)，目的在于盡可能保證“量體裁衣”,既不治療過(guò)度又不治療不足，其依據(jù)主要為：2.1.1 關(guān)于NCCN(國(guó)立綜合癌癥網(wǎng))（1） a not-for-profit alliance of 21 of the worlds leading cancer centers為21個(gè)世界首要癌癥中心的非盈利性聯(lián)盟組織 （2）The leadership and expertise of clinical pro

9、fessionals at NCCN Member Institutions 臨床專家組成的委員會(huì) （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(wù)：不斷改進(jìn)患者生活質(zhì)量，治療效果及效率-改善生存（4） The development of NCCN information is based upon the independ

10、ent evaluation of available scientific evidence integrated with the expert judgment of leading clinicians. 由首要的臨床專家們對(duì)提供的科學(xué)證據(jù)進(jìn)行獨(dú)立評(píng)估并結(jié)合專業(yè)判斷，據(jù)此每年改進(jìn)NCCN“指南” 2.1.2 Clinical Trials 指南內(nèi)容根據(jù)-臨床試驗(yàn)結(jié)果 （1） The NCCN believes that the best management for any cancer. Patient is in a clinical trial. Participation in

11、 clinical trials is especially encouraged.（2） All recommendations are Category 2A unless otherwise specified（3） NCCN Categories of Evidence and Consensus: NCCN 臨床證據(jù)及評(píng)判意見(jiàn)一致性的分類(lèi) 如下表Category of Evidence and Consensus臨床證據(jù)及小組評(píng)判分類(lèi)Quality of Evidence證據(jù)的可靠性 Level of Consensus評(píng)價(jià)的一致性1High: high-powered random

12、ized 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 from phase or large cohort studies to individual practitioner experience. In many instances, the retrospective

13、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-uniform3AnyMajor disagreement2.1.3 Safeguards for Eliminating Biases 消除指南偏差 2.1.3.1 Two safeguards listed as follow: p

14、anels reflecting all schools of thought for a particular tumor, and the process of iteration and feedback 廣泛性及反復(fù)討論 2.1.3.2 To address bias is the presentation of new NCCN Guidelines at the annual meeting, where meeting attendees are invited to provide both oral and written comments on the guidelines

15、.每年年會(huì)根據(jù)臨床試驗(yàn)的結(jié)果，討論對(duì)指南的不同意見(jiàn)形成新指南 2.1.4 指南形成過(guò)程 NCCN Guidelines Development Process“指南”指導(dǎo)委員會(huì)挑選主要內(nèi)容 Guidelines Steering Committee Selects Topic 某指南專門(mén)小組 Guideline Panel Selected 形成某指南一稿 Preliminary Pathway Derivation 多中心復(fù)核 小組材料討論按NCCN方法當(dāng)歸納 Institutional Review Collection 采集補(bǔ)充 Guideline Revision 指南修正 Final

16、 Guideline 指南定稿 Continuous Review 繼續(xù)復(fù)核2.1.5 NCCN 開(kāi)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 Therapy復(fù)發(fā)治療、補(bǔ)救治療Salvage/Recurrence Therapy 對(duì)癥、支持處理步驟Symptom Management/ Supportive Care Pathways篩查Screening危險(xiǎn)性評(píng)估RiskAssessment分級(jí)Triage特異性評(píng)估SpecializedEvaluat

17、ion特異性干預(yù)SpecificIntervention再次評(píng)估Reevaluation隨訪Follow-up2.1.2 病理診斷是關(guān)鍵，除組織形態(tài)學(xué)外，還常需分子病理學(xué)（分子遺傳病理，免疫組化病理）嚴(yán)格重視病理診斷應(yīng)與臨床診斷一致。存在下列兩種情況，可在無(wú)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(dǎo)致較嚴(yán)重后果或死亡b 良性病變可能性小2.1.3 在TNM分類(lèi)的基礎(chǔ)上分期（以胃癌為例2009）2.1.3.1 2.1.3.22.1.3.32.1.3.42.1.4 體能狀態(tài)分級(jí) 2.2 應(yīng)用化療的四種目的2.2.1 Adjuvant chemotherapy 輔助性化療 （根治

18、性手術(shù)/放療后）2.2.1 Primary/Neuadjuvant chemotherapy:起始/新輔助化療（局部根治性手術(shù)/放療前，少數(shù)疾病作為主要治療）2.2.3 局部治療（如介入，腔內(nèi)應(yīng)用等）2.2.4 晚期疾病的姑息治療2.3 化療毒副反應(yīng)及其處理2.3.1 推薦WHO或美國(guó)NCI的不良反應(yīng)分類(lèi)，分1，2，3，4度，1，2度為可允許反應(yīng)，3度應(yīng)避免，發(fā)生后應(yīng)停藥，日后需再行化療要改善調(diào)整劑量，4度則需立即停藥，急救及時(shí)，慎重處理。2.3.2 通過(guò)用藥方式削弱蒽環(huán)類(lèi)的毒性并提高療效。 2.3.3 抗惡心嘔吐處理原則 抗5HT3 受體拮抗劑（如樞復(fù)寧類(lèi)）最可靠，無(wú)禁忌下應(yīng)與地塞米松合用，

19、以化療前0.5-1小時(shí)開(kāi)始用最佳，化療結(jié)束后再用1-3日，主要針對(duì)急性嘔吐。 Aprepitant(抗敏吐/阿瑞匹坦)，為神經(jīng)激肽-1受體拮抗劑，對(duì)急性，特別是延遲性嘔吐均有效，可與上方案聯(lián)合應(yīng)用。 未用化療前的“預(yù)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(shí)一次。（可有遺忘，精神錯(cuò)亂等副作用）?；虬捕?0mg化療前2小時(shí)肌注或靜注 2.4 時(shí)辰化療 以下摘自Michcel perry: The chemotherapy sorce book (2nd Edition）2.4.1 時(shí)辰影響水平：生理和病理，系統(tǒng)和器官，細(xì)胞和分子2

20、.4.2 時(shí)辰化療的需要：不少非時(shí)辰化療方案對(duì)平衡宿主腫瘤損害，毒性和治療指數(shù)有欠缺。2.4.3 抗癌治療時(shí)辰依賴性的基礎(chǔ)2.4.3.1 時(shí)辰性藥理動(dòng)力學(xué)：吸收，分布，代謝，排泄2.4.3.1.12.4.3.1.22.4.3.2機(jī)體組織細(xì)胞動(dòng)力學(xué)：S時(shí)相特異性藥物對(duì)胃腸道及骨髓損害以夜間給藥為輕。2.4.3.3 內(nèi)分泌及免疫：腎上腺皮質(zhì)激素，T，B，NK細(xì)胞及各種免疫反應(yīng)。2.4.3.4 癌瘤時(shí)辰特點(diǎn)2.4.3.4.1 2.4.3.4.2 癌瘤血流時(shí)辰性，實(shí)驗(yàn)表明皮下癌瘤活躍時(shí)相與非活躍時(shí)相供血相差一倍，但不伴瘤體積變化，此時(shí)給藥化療療效增強(qiáng)。2.4.3.4.3 時(shí)辰治療對(duì)療效與毒性的影響2.

21、4.3.4.3.12.4.3.4.3.2 2.4.3.4.3.32.5 如何預(yù)防繼發(fā)癌2.5.1 Define the risk of recurrence and tailor the intensity of cancer therapy: Lowering the dose of treatment for low risk groups is probably the important way to prevent secondary cancer 2.5.2 Avoid radiation therapy2.5.2.1 This has been successful in chi

22、ldhood ALL where intrathecal chemotherapy has been substituted for radiation2.5.2.2 Hodgkins disease and non-Hodgkins lymphoma:where certain groups of patients have been found to survive just as well with chemotherapy alone as with chemotherapy plus radiation therapy2.5.3 Avoid drugs with high carci

23、nogenic potential2.5.3.1 This is difficult to do since all chemotherapy drugs are carcinogenic 2.5.3.2 Etoposide is associated with a relatively high incidence of myelodysplasia and acute myeloid leukemia and in some instances other drugs could be used instead2.6化/放療心血管并發(fā)癥2.6.1 Edward T.H. etc; Card

24、iovascular complications of Cancer Therapy Diagonsis, Pathogenesis, and Management (Circulation. 2004; 109 : 3112- 3131.)2.6.1.1 Cardiotoxic Syndromes Associated With Chemotherapeutic Agents（1） Agents associated with myocardial depression Anthracyclines Mitoxantrone(Novantrone) Cyclophosphamide(Cyto

25、xan)high dose Trastuzumab(Herceptin) Ifosfamide(Ifex) All-trans retinoic acid(Tretinoin)（2） Agents associated with ischemia 5-FU (adrucil) Cisplatin (platinol) Capecitabine (Xeloda ) IL-2（3） Agents associated with hypotension Etoposide(Vepesid) Paclitaxel(Taxol) Alemtuzumab (Campath) 阿侖單抗 抗CD52 Cetu

26、ximab (Erbitux) 愛(ài)必妥抗表皮生長(zhǎng)因子受體（HER1) Rituximab (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)（5）Agents associated with other toxic e

27、ffects Cardiac tamponade 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 Poin

28、tes : arsenic trioxide(Trisenox) Pulmonary fibrosis : bleomycin(Blenoxane)2.6.2 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 dr

29、ugs.Systolic dysfunction and pericarditis with cyclophosphamide.LV dysfunction with anthracyclines2.6.2.2Administering anthracyclines by continuous infusion over 24 to 92 hours rather than by rapid intravenous infusion could reduce the cardiotoxicity of these drugs.Busulfan causes tachyarrythmias, h

30、ypertension or hypotension, and LV dysfunction when injected but not when taken orally .The 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 .(interval )The combination

31、 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.2.6.2.3Advanced age is a known risk factor for anthracycline cardiotoxicity C

32、ardiovascular 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 patients with lymphoma. Alemtuzumab be

33、ing associated with LV dysfunction in patients with mycosis fungoides.2.6.3 cardiotoxicity Associated With Radiation Therapy2.6.3.1 Radiation-induced heart disease is higher in patients given high doses of radiation therapy concurrent with doxorubicin.2.6.3.2 Vascular injury from radiation therapy c

34、an be silent; approximately 50% of asymptomatic patients develop new myocardial perfusion defects.2.6.3.3 Sudden death in patients is thought to result from diffuse intimal hyperplasis of all cornary arteries or from significant left main stenosis. The mean interval for developing CAD (coronary arte

35、ry disease ) after radiation therapy is approximately 82 months.2.6.3.4 Radiation therapy also causes fibrous thickening of the pericardium, ranging from 2 to 145 months. Pericardial effusion is typically an early presentation. Whereas pericardial constriction is a late manifestation. Usually appear

36、ing 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.2.7預(yù)防與處理2.7.1 Monitoring Cardiovascular Toxiciity2.7.1.1 B-type natriuretic peptide (BNP) (B

37、型利鈉肽 腦鈉素） has been shown to be elevated before the development of LV dysfunction.2.7.1.2 Provocative testing with exercise or dobutamine echocardiography may be sensitive for the early detection of subclincial cardiomvonpathy and may provide an opportunity for therapeutic intervention before the dev

38、elopment of overt LV dysfunction.2.7.1.3 Diastolic dysfunction is an early sign.2.7.1.4 Fractional shortening and LV ejection fraction are not sensitive for the early detection of preclinical cardiac diaease.2.7.2 Strategies to Reduce Cardiovascular Toxicity and Manage Complications2.7.2.1Anthracycl

39、ine 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。3.5.2 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(shù)前同步放化療，（不能切除行常規(guī)同步放化療）。3.5.2.2 B(T3N0),A,B(T3-4,N1),可切除者術(shù)前同步放化療，（不能切除者常規(guī)同步放化療）3.5.2.3 推薦化療方案 （ NCCN 2009）3.6 乳癌3.6.1 可行新輔助化療者為：（一般3-4周期，無(wú)效換方案）3.6.1.1 要求保乳并且符合保乳手術(shù)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,M03.6.1.3 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)，C