9 tumor+chemotherapy english +version imp

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Tumor Chemotherapy

Sun Yet-san University Cancer CenterRui-Hua Xu, Zhi-Ming LiE-mail: [email protected]

[email protected] Tel: 8734 3356

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Tumor chemotherapy?

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2.Just heard.

3.Never heard.

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Definition

√Tumor chemotherapy

A systemic therapy, kill cancer cells with anticancer drugs.

Narrow-sense： cytotoxic drugs

Broad-sense： medical oncology（ chemotherapy, endocrine therapy, immunotherapy etc. ）

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Basic theories of chemotherapy

History of chemotherapy and the role it plays in the cancer treatment

Tumor cell cycle kinetics Classification and mechanism of anticancer

drugs Adverse effects of anticancer drugs Clinical application of chemotherapy

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Development of Chemo-drugs

Nitrogen Mustard for lymphoma

40s

50s

MTX for hematological malignancies & children’s ALL

70s

DDP、 ADM—palliative chemotherapy transition to curative chemotherapy, medical oncology established

80s

Adjuvant/Neo-adjuvant chemotherapy

90s

21st

Biological Response Modifier ，supportive care ，High dose chemotherapy＋ HSCT

Molecular target drug

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Milestones of anticancer therapy

• The latter half of the 20th century

Cytotoxic drugs took the predominant position with a

continuous appearance of new agents.

• The late 19th century ～ 21st century

Cytotoxic drugs kept developing

Molecular target drugs

Biotherapy and gene therapy develop rapidly

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Achievements of chemotherapy• A. Several diseases may be cured from incurable

diseases : Lymphoma, testicular cancer, acute lymphocytic leukemia, chorio carcinoma, etc.

• B. Solid tumor’s palliative chemotherapy is still

unsatisfied, but keeps improving :Breast cancer, NSCLC,

gastric cancer, colon cancer, NPC, etc.• C. Adjuvant chemotherapy reduces the relapse rate and

improve the efficacy: Breast cancer, colorectal cancer,

NSCLC, osteosarcoma, etc.• D. Neo-adjuvant chemotherapy increase resection rate,

reduce disability:breast cancer, rectal cancer, Laryngeal

cancer,etc.

Comparison of children’s ALLHodgkin’ LymphomaTesticular tumor

100100

8080

6060

4040

2020

00

0 6 12 180 6 12 18

CTCT BSCBSC

Chemotherapy of Advanced NSCLC Progress of mCRC

BSC 1980s

5-FU/LV 1990s

5-FU/LV Civ 1990s

5-FU/LV/Irino 2000

5-FU/LV/Oxal 2000

FOLFOX/ FOLFIRIFUFOX 2001

FOLFOX/IRI+TargetTherapy 2004

Adjuvant chemotherapy of breast cancer Adjuvant chemotherapy of NSCLC

MOSAIC trial for CRC

Adjuvant chemotherapy of colorectal cancer

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Basic theories of chemotherapy



drugs Adverse effects of anticancer drugs Clinical application of chemotherapy

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Tumor

Body Drug

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Tumor

Body Drug

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Cell cycle kinetics

Cell cycle G1 DNA pre-synthetic phase

S DNA synthetic phase

G2 DNA post synthetic phase

M mitotic phase

Cells without proliferationability

G0（ resting phase ）

Death

Cells in proliferation cycle

Refers to a process from theformer ending of mitosisto the next ending.

Regulated by cyclins（ CKDs、 CDKIs)

G1

M

G2

S

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Tumor biology —growth kinetics

• Non-proliferation group Proliferation group

cells without

proliferation capacity

G0（ quiescent cell ）

√√Growth fractionGrowth fraction（（ GFGF）） :: The percentage of the cells in The percentage of the cells in

active proliferation phase in total cells.active proliferation phase in total cells.

Growth part

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Tumor biology —growth kinetics

• Different types of tumor cells have different GF

• The higher the GF， the more sensitive tumor to chemotherapy, it will be much easier to cure the tumor. (Lymphoma’s GF is 90%）

• Effective treatment decreases the number of proliferating cells， but cells in G0 phase may re-enter the proliferation phase that causes the tumor relapse.

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Tumor biology － growth kinetics

Doubling time

(DT): The time tumor cells need to increase twice of the total amount and volume

NormalNormalcellcell

DividingDividing

MalignantMalignanttransformationtransformation

2 2 cancercancercellscells

DoublingDoubling 4 4 cellscells

DoublingDoubling

8 8 cellscells

DoublingDoubling

16 16 cellscells

1 1 million cellsmillion cells(20 doublings)(20 doublings)undetectableundetectable

1 1 billion cellsbillion cells(30 doublings)(30 doublings)lump appearslump appears

1 1 trillion cellstrillion cells(40 doublings – 2 lb/1kg)(40 doublings – 2 lb/1kg)

41 – 4341 – 43doublingsdoublings— Death— Death

时间

指数生长

癌瘤

正常细胞产生 =细胞丢失

稳定态

Gompertzian 生长对数细胞数

时间

指数生长

癌瘤


稳定态


时间

指数生长

癌瘤


稳定态


Time

Exponential Growth

tumor

normal cell produce=cell loss

Stable state

Gompertzian growth

cell produce > cell loss

lLog ofCells

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Tumor biology—loss of tumor cells

• Lack of blood supply, offspring cells’ genetic variation, cells shedding from the surface of tumor—loss of tumor cells.

• Unlike the normal tissue, tumor’s growth always exceeding its loss， which leads to tumor progression.

• Severity of tumor loss various in different types of tumor. The more it loss, the slower it grows and vice versa.

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Tumor

Body Drug

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Tumor biology Total kill

• “To cure cancer patient, we must eliminate all the tumor cells in the body”—the important basic theory of curative chemotherapy.

• Anticancer drugs kill tumor cells followed the “first order kinetics”： kill a proportion, not a number of tumor cells each time. So multiple courses are needed to kill the tumor.

• Clinical complete remission does not equal to cure.

1012

106

1012

1011

1010

109

108

107

106

Anticancer drug’s killing kinetics

The number

of tumor cells

in vivo

10101212

（（ 1kg)1kg)

101099

（（ 1g)1g)

101066

（（ 1mg)1mg)

101033

（（ 1ug)1ug)

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Clinical detectionClinical detection

Clinical cureClinical cure

Host immuneHost immune

clearanceclearance

Induce Consolidation Maintenance Induce Consolidation Maintenance CureCure

Tumor reaction to anticancer drugs

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Complexity of tumor’s drug resistance

Pseudo-resistance： Blood-brain Barrier、 Blood-testis barrier Tumor biology MDR Congenital Interstitial pressure Hypoxia Tumor factors Goldie-Coldman Acquired Simon-NortonTrue resistance MDR Tumor heterogeneity Body factors ： Drug targeting enzyme, metabolic enzyme

Tumor drugresistance

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Tumor multiple drug resistance (MDR)

•MDR：– Def：When it resists to one anticancer

drug, tumor cells will show cross resistance to many other types of drugs , not only those shared similar mechanism.

– Often seen in those naturally originated drugs, like the botanical alkaloids and antibiotics.

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Mechanism of MDR

Extra cellular Intracellular

ATPATP

P-glycoproteinP-glycoprotein170170 ATPATP

DrugDrug

DrugDrug

Cell membraneCell membrane

22NEJM 2003 348:538-549

Target enzyme and efficacy of anticancer drug

23Clin Cancer Res 4139 2006;12(14) July 15, 2006

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Basis theories of chemotherapy



drugs Adverse effect of anticancer drugs Clinical application of chemotherapy

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Tumor

Body Drug

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Drug• Classification ：

(1) According to cell cycle:

1. Cell cycle non-specific agents

2. Cell cycle specific agents

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Cell cycle non-specific agents

100 S 细胞存活 R 率% 剂量

S: Slow growth (normal cell) R: Rapid growth (tumor cell)

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Cell cycle specific agents

100 S 细胞存活 R率% 剂量

S: Slow growth (normal cell) R: Rapid growth (tumor cell)

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The connection of anticancer drug’s effect and cell cycle

Antimetabolite

Antibiotic

S(2-6h) G2

(2-32h)

M(0.5-2h)

Alkylating

agent

G1

(2-h)

G0

Vinblastine

Anti-mitosis drugs

Taxoids

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Classification of anticancer drugs

(2) According to mechanism ：• Alkylating agent • Antimetabolite • Antibiotic• Tubulin inhibitor• Topoisomerase inhibitor• Hormones• Molecular target drug

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Alkylating agent

• Nitrogen mustards：HN2、CTX， IFO， chlorambucil（ leukera

n ）， L-PAM(Melphalan ）• Nitrosoureas ：CCNU，BCNU，Me-CCNU

• Alkyl sodium sulfonate ：myleran

• Triazine ：DTIC

• Ethyleneimine：TSPA

• Metallic salts： cisplatine， carboplatine ， oxaliplatine

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Alkylating agent Mechanism ：

DNADNA double double strandsstrands

inhibitinhibitDNA replicationDNA replication

inhibitinhibitDNA replicationDNA replication

C+C+ C+C+

Alkylating agent has active R-CH2-R-CH2-，， it forms a cross linking with DNA molecularDNA molecular or between DNA molecularDNA molecular and proteinprotein by foralkylation, which causes cell death、 gene mutation or carcinogenesis.

Destroy DNA structure directly, has strong toxicity to both proliferate or non-proliferate cells——Cell cycle non-specific Cell cycle non-specific agentsagents

Important to the slow growth tumor，， with precipitous dose-response curve.

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Alkylating agent Cyclophosphamide

CTX

4-4-OH CTXOH CTX

aldophosphamidealdophosphamide

phospho ramide mustardphospho ramide mustard

4-4-keto cyclophosphamideketo cyclophosphamide

Carboxyl phosphamideCarboxyl phosphamide

AcroleinAcrolein

Hepatic CytochromeHepatic Cytochrome P 450P 450

activatedactivated

Cell toxicityCell toxicityToxicityToxicity

inactivateinactivate

AcetaldehydeAcetaldehyde

dehydrogenasedehydrogenase

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Platinum drugsPlatinum drugs

Pt(II)Pt(II)

NHNH33

NHNH33

Pt(II)Pt(II)

NHNH33

NHNH33

+ 2+ 2HH22OO

CisplatinCisplatin Reactive complexReactive complex

+ 2+ 2ClCl-- PtPt GG

GG

ClCl

ClCl

HH22OO++

HH22OO++

DNADNAStrandStrand

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Platinum drugs

• DDP side effects ：• Kidney toxicity（ dose limiting): Mainly causes the

renal tubular damage. Large dose usage needs hydration

and diuresis.

• Severe vomiting， but less myelosuppression.

• Ototoxicty and peripheral neurotoxicity.

• Indication： common used broad-spectrum anticancer

drug， important composition in many combination

chemotherapies.

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Anti-metabolite anticancer drugs

• folic acid antagonist ：MTX

• miazines ： 5-Fu， fluorofur ， furtuion， Capacitabine

• cytidine： Ara-C， Gemcitabine

• purines ： 6-MP ， 6-TG

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• Mechanism--Has similar structure to the normal metabolites, competitively inhibits the main enzymes of nucleic acid metabolismand replace the precursor materials for DNA or RNA synthesis,

thus affect DNA synthesis

-- Interference with nucleic acid synthesis, most effective in

Phase S—cell cycle specific， little effect on non-proliferating cells

-- The curve flattened when dose increased. No effect on stem cells, short and slight myelosuppression

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Dihydrofolate

Reductase

METHOTREXATEMETHOTREXATE ((MTX)MTX)

FHFH22 FHFH44

UracilUracil + + NN5-105-10 methylene FH methylene FH44

deoxynucleotidedeoxynucleotide

（（ dUMPdUMP））5-5-fluorouracilfluorouracil (5-(5-FU)FU)

Purine Nucleotide

thymidinethymidine deoxynucleodeoxynucleo

tidetide ((dTMP)dTMP)

Thymidylate SynthaseThymidylate Synthase ((TS)TS)

fluorouracilfluorouracil

deoxynucleotidedeoxynucleotide （（ F dUMPF dUMP））

DNADNApolymerase

Cytarabine ((Arac)Arac)

GemcitabineGemcitabine

6MP、 6TG

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Antibiotic anticancer drugs

Double strand dissociationDouble strand dissociation

Interfere DNA transcription Interfere DNA transcription and mRNA synthesisand mRNA synthesis

Anthracycline Anthracycline

antiboticsantibotics

insert to the base pair near the DNA double strand

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Antibiotic anticancer drugs• Side effects of anthracycline : cardiac toxicity (dose-

limiting toxicity) • Cumulative dose of doxorubicin incidence of congestive heart failure

450-550mg/M2 1-2% 550mg/M2 1-4% 600mg/M2 30%• With a history of mediastinal radiotherapy or hypertension, the

application of CTX will increase the cardiac toxicity. • Monitoring Methods: cardiac nuclide scan or cardiac

ultrasound to observe the changes of left ventricular ejection index.

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Antibiotic anticancer drugs

• Others: dactinomycin, bleomycin, mitomycin

• Bleomycin may cause the pulmonary fibrosis, the cumulative dose

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Tubulin inhibitorVinblastine category

• AntimitoticAntimitotic——binding with tubulin , binding with tubulin , block tubulin block tubulin polymerizationpolymerization，， stop the cell mitosis at the mid phase.stop the cell mitosis at the mid phase.

• IncludeInclude：： Vinblastine, Vincristine, Vindesine,etcVinblastine, Vincristine, Vindesine,etc..

• Common side effects are bone marrow toxicity andCommon side effects are bone marrow toxicity and neurotoxicityneurotoxicity

Taxadiene category ::

：：• Antimitotic - Antimitotic - block tubulin depolymerizationblock tubulin depolymerization, , interfere with mitosisinterfere with mitosis

• IncludeInclude：： Taxol, TaxotereTaxol, Taxotere

• Side effectsSide effects：： allergy, bone marrow suppression, allergy, bone marrow suppression, neurotoxicity, hair loss, etc.neurotoxicity, hair loss, etc.

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Interfere tubulin polymerizationInterfere tubulin polymerization :: ccolchicineolchicine

VinblastineVinblastine

block tubulin depolymerizationblock tubulin depolymerization :: TaxoidsTaxoids

Tubulin inhibitor

tubulintubulin tubuletubule

2020nmnm

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Anti-mitosis anticancer drugs

Centromere

Soluble tubulin dimer

Nuclear membrane fragments

TaxoidsTaxoidsPromote tubulin polymerizationPromote tubulin polymerizationPrevent tubulin depolymerizationPrevent tubulin depolymerization

VinblastineVinblastine inhibit spindle fibers’ formationinhibit spindle fibers’ formation

Prometaphase of mitosisPrometaphase of mitosis

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Topoisomerase inhibitors

• Topoisomerase I inhibitors： camptothecin:

CPT-11, Topotecan • Break the DNA single strand, interfere DNA

replication• Side effects : CPT-11 causes acetylcholine

syndrome, delayed diarrhea, nausea, vomiting, bone marrow suppression

• Indication： colon cancer, SCLC, ovarian cancer

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Topoisomerase inhibitors

• Topoisomerase II inhibitors ： etoposide：teniposide

• Break the double strands of DNA, interfere with DNA replication

• The main toxicity is myelosuppression, transient hypotension may occur during rapid infusion .

• Indication ： broad-spectrum anti-cancer drugs , testicular tumor, SCLC, refractory NHL

Topoisomerase

Cells in S-phase

DNADNA DNA replicationDNA replication

DNA rotaDNA rotating ting along its axisalong its axis

interfere DNA interfere DNA replicationreplication

Double-strand Double-strand torsion increasedtorsion increased

Topoisomerase

Attached double-stranded DNA， cut through the DNA strand transiently， the torsion disappeared， thencatch the rotated DNA again， re-adhesion the DNA strand

Topoisomerase I inhibitors

Topoisomerase I inhibitors combined with TOPO I-DNA

complexcomplex

combination of replication combination of replication forkfork

& & Breaking of DNA single Breaking of DNA single strandstrand

Interruption of the cell cycleInterruption of the cell cycleCell deathCell death

Topoisomerase I inhibitors

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嘌呤合成嘧啶合成 6－MP，6－TG HU(抑制嘌呤环的合成和核苷酸的转变) 核苷酸 (抑制核苷酸还原酶)

MTX 5-FU(抑制嘌呤环合成和 dTMP合成) 脱氧核苷酸 (抑制 dTMP合成)

Ara-C BLM (抑制 DNA多聚酶) DNA (损伤 DNA并阻碍修复)

烷化剂， ADR,DNA,Act-D (与 DNA交叉连结) RNA (嵌入 DNA，抑制 RNA合成)

L-ASP 蛋白质合成紫杉醇类 (使 L门冬酰胺水解) (抑制微管解聚)

长春碱类有丝分裂 (抑制微管聚合)

Mechanism of anticancer drugsMechanism of anticancer drugs

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Molecular target drugs

• Specifically act on the key molecular in cancer cells’

lives、 proliferation、 invasion and metastasis. (High

selectivity ）• Broad targeting: cell membrane antigen, EGFR,

VEGFR, tyrosine kinase, Farnesyltransferase ... ... • Various of structures: small-molecule compounds,

monoclonal antibodies (anti-rat, chimeric, humanized), antisense oligonucleotide , natural products; low toxicity, cooperate with chemotherapy, radiotherapy

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Common target drugs

Name Trade name Main targets Structure Indication

Imatinib Gleeve Bcr/Abl, c-kit, PDEFR

Small Molecule

Compounds CML GIST

Retuximab MabThera CD-20( B limphocyte)

Chimeric Antibody NHL

Transtuzumab Herceptin HER2/neu Human antibody Breast cancer

Gefitinib Iressa EGFR-TKSmall Molecule Compounds

NSCLC

Cetuximab Erbitux EGFR Chimeric AntibodyColorectal, head & neck

Erlotinib Tarceva EGFR-TKSmall Molecule Compounds

非小细胞肺癌NSCLC

Bevacizumab Avastin VEGF Human antibody Colorectal Ca

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Gefitiniberlotinib

Anti-EGFR 2: Herceptin Anti-EGFR 1: Cetuximub

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Tumor

Body Drug

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Adverse effect of anticancer drugs• Short term

GeneralityGenerality ①① MyelosuppressionMyelosuppression suppressionsuppression

IndividualityIndividuality

②②Gastrointestinal-tract side effectGastrointestinal-tract side effect ③③Hair lossHair loss ④④Local stimulationLocal stimulation（（ drug extravasationdrug extravasation ）） ⑤⑤ Allergic Allergic ReactionReaction

①①Cardiac toxicityCardiac toxicity ②②Lung toxicityLung toxicity ③③Neurological toxicityNeurological toxicity ④④Liver toxicityLiver toxicity ⑤⑤Kidney toxicityKidney toxicity

• Leukopenia: infection (anti-bacterial treatment and the Leukopenia: infection (anti-bacterial treatment and the application of G-CSF)application of G-CSF)

• Erythrocytopenia: anemia (RBC infusion and the Erythrocytopenia: anemia (RBC infusion and the application of Epo)application of Epo)

• Thrombocytopenia: haemorrhage (platelet infusion and the Thrombocytopenia: haemorrhage (platelet infusion and the application of Tapplication of TPO)PO)

• Nausea, vomiting :5-HT3 receptor antagonistNausea, vomiting :5-HT3 receptor antagonist

• Oral Ulcer: mouthwash, anti-bacterial treatmentOral Ulcer: mouthwash, anti-bacterial treatment

• Diarrhea, abdominal pain: anti-bacterial treatment, water-Diarrhea, abdominal pain: anti-bacterial treatment, water-electrolyte balanceelectrolyte balance

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Adverse effect of anticancer drugs

• Long term ⑴ Carcinogenesis

⑵ Infertility (3)Growth retardation

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Clinical application of chemotherapy goals of chemotherapy

• Curative Chemotherapy

• Adjuvant Chemotherapy

• Neoadjuvant Chemotherapy

• Palliative Chemotherapy

• Investigative Chemotherapy

√√

√

√

√

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Clinical application—curative chemotherapy

• Tumors can be cured by chemotherapy ： Acute leukemia, non-Hodgkin's lymphoma,

HD, testicular germ cell cancer, ovarian cancer, child nephroblastoma, embryonal rhabdomyosarcoma, Ewing's tumor etc.

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Clinical application—curative chemotherapy

• Applicable to those tumors which may be cured by chemotherapy

• Select the recognized standard combination chemotherapy

• Adequate course and full dosages • Do not arbitrarily extend the intervals of

chemotherapy • Intensive supportive care, prevent and treat the

complications of chemotherapy

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Clinical application—adjuvant chemotherapy

• Radical surgery, eliminating sub-clinical micro-metastasis, is part of the curative treatment.

• Postoperative chemotherapy should be given as soon as possible

• Choose standard regimens• Breast cancer， osteosarcoma, lung cancer,

colorectal cancer and other solid tumors of children, etc.

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Clinical application—neo-adjuvant chemotherapy

• Neo-Adjuvant Chemotherapy before surgery or radiation therapy

• Increase resection rates, reduce the surgical injury, eliminate the sub-clinical metastasis, investigate the body reaction of chemotherapy

• Choose standard regimens• Suit for the head and neck cancers, rectal

cancer, osteosarcoma

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Clinical application—palliative chemotherapy

• To relief symptoms ， prolong survival, improve quality of life for terminal patients

• Non-curative chemotherapy, must balance the advantages and disadvantages of chemotherapy

• Advanced non-small cell lung cancer, gastric cancer, liver cancer, colorectal cancer, renal cancer, malignant melanoma, pancreatic cancer, etc.

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Balance of chemotherapy efficacy and toxicity

EfficacyEfficacy SafetySafety

Strategy for the reasonable application of chemotherapy

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Patient’s survival time and quality of life after treatment

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Clinical application----investigative chemotherapy

• Definition ： Clinical investigations of new drugs or new regimens.

• Content ： purpose， scheme ， observation, evaluation

• Principles: low toxicity, effective and comply with medical ethics

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Clinical application of chemotherapy—the principle of Rational Drug Use

• The principle for selecting regimen :standard regimen as first choice.

• Principle of Combination Chemotherapy– Effective single drug– Various mechanisms and phases– Various toxicity– Proven to be effective in clinical application

√

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Research for enhancing the effect of systemic chemotherapy

• Development of new cytotoxic drugs• Application of molecular target drugs• Raise the dosage of chemotherapy drugs• Overcome drug-resistance of tumor cells• Biological Treatment• Gene Therapy

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PROGRESS IN MEDICAL ONCOLOGYPROGRESS IN MEDICAL ONCOLOGY1975 → 2000 → 20251975 → 2000 → 2025

MOLECULARMOLECULARMEDICINEMEDICINE

EVIDENCE-BASED MEDICINEEVIDENCE-BASED MEDICINE

SMALL, PILOT TRIALSSMALL, PILOT TRIALS

PPRROOGGRREESSSS

19751975 19801980 20002000

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Conclusions

• Definition of chemotherapy• Cancer Biology ： cell cycle 、 growth

fraction(GF) 、 doubling time (DT)• Classification of anticancer drugs： cycles and

mechanism• Adverse effect of anticancer drugs• Clinical application of anticancer drugs

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Thank Thank you!you!

9 tumor+chemotherapy english +version imp

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