CANCER CHEMOTHERAPY

(Lecture Outline For Medical Students)

管 忠 震

Cancer Chemotherapy

• (1) The role of chemotherapy in cancer treatment

• (2) Current status of cancer chemotherapy: How effective it is?

• (3) Mechanism of cancer chemotherapy: a brief review

• (4) Difficulties in cancer chemotherapy: How to overcome?

• (5) New developments

A Brief Review of Natural History of Cancer

• Normal somatic cell• mutation• Malignant change• • Cancer cell Proliferate• (Mitosis)

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Doubl ing

Cell mitosis:

• DNA

• Synthesis Mitosis

• RNA

• S phase M phase

Cancer cell: Number Increasing• Cancer in situ

• T

• Local tumor mass

• Local infiltration & extension

• Locally advanced

• N Lymphatic spread: LN

• M Hemangial (Systemic spread):

• Remote metastasis

Cancer ChemotherapyTNM Staging System Progression of Cancer

T1

N0M0 Localized Cancer Early, localizedT2

T3

N0M0 Infiltration & Local extension Locallly advancedT4

TxN1M0

N2 Regional LN involvement Reginal N3

TxNxM1 Remote or Systemic metastasis Metastatic

Cancer, Treatment of Choice

If Surgery not possible,

Radio therapy

Chemotherapy

Radio + Chemo (Radio-sensitizer)

Chemo Radio Radio, Chemo Surgery (Neo. Adjuvant Chemotherapy)

If Surgery possible,

Post-operative Radio or Chemo (Adjuvant Chemotherapy)· Reginal: Radiotherapy Chemo (Adjuvant) En-bloc Surgery, if possible therapy· Metastatic Cancer: Chemotherapy (Palliative or Curative)

• Localized Cancer: Surgery

• Locally Advanced:

Role of Chemotherapy in Cancer Treatment

• (1) Metastatic Cancer: Palliative or• Curative Chemotherapy• (2) Adjuvant Chemotherapy:• to erradicate or control micro-metastasis• (3) Neo-adjuvant Chemotherapy• (Induction Chemotherapy) to make Surgery of RT possible

• to alleviate surgical damage• to eradicate micro-metastasis

• (4) Hematological Malignancies:• Primary Treatment

In Localized or Regional Cancer Cases

Micro-Metastasis May occur

(Sub Clinical Metastasis)

e.g.

(1) Stage II Breast CancerBreast Cancer with (+) Axillary L.N. (N1 or N2)Mo, Surgery PossibleActually, Micro Metastasis present LN<4, 50%(Micro-Met+) LN>4, 80%(Micro-Met+)

Recurrence following SurgeryAdjuvant Chemotherapy necessary

(2) Osteogenic Sarcoma of Lower ectremities

Chest X-ray(-)Amputation, 80% Recurrence Rate Reason: Micro Metastasis presentTreatment: Surery + Intensive Adjuvant Chemotherapy

Efficacy of Chemotherapy to Cancers

Chemotherapy Curable Cancers

• Childhood:• ALL 70%• NHL >50%• Burkitt’s Lymphoma >50%• Wilm’s Tumor >50%• Ewing’s Sarcoma >50%• Embrynal >50%• Rhabdomyosarcoma

· Adult:

· Chorio-Carcinoma 90%

· Testis Cancer >75%

· Hodgkins’ Disease 70%

· Aggressive NHL >50%

· AML 25%-50%

· Ovarians Cancer 10%-20%

Chemo-Resistant (Insensitive) Cancers

Non-Small Cell Lung Cancer

G.I. Cancers

Pancreatic Cancer

Melanoma

Mechanism of Cancer Chemotherapy(Cytostatic Drugs)• Anti-proliferation

– (1) Blockage DNA Synthesis• Blockage purined pyramidine synthesis• Inhibit DNA polymerase

– (2) Direct Damage to DNA• Breakage of DNA chain• Cross-linkage, inhibit depolarization

– (3) Inhibit Transduction (DNA RNA)– (4) Spindle toxin Mitosis damage– (5) Inhibit topoisomerase

Difficulties in Cancer Chemotherapy

(1) Non-dividing Cancer Cells (Go cells)

• Growth Fraction (GF) and sensitivty

• Insensitive Cancers: – Non-small Cell Lung Cancer– G-I Cancers– Liver Cancer, etc

• Go Cells in Sensitive Cancer: Recurrence

(2) Proliferating Normal Cell: Damage

• Myelo Suppression:– Granulocytopenia Infection– Thrombocytopenia Hemorrhage– RBC anemia– Lymphocytopenia Immune Suppression

• Mucous Epith Cells Stomatitis G-I reactions

• Germ Cells Inferlity

• Foetus Teratogenic, Abortion

• (3) Other Organ Toxicity

• Cardiac, Hepatic, Renal, etc.

• Pulmonary

• (4) Drug Resistance

Methods of Improvement:

• Component Transfusion

• Protected Environment (life Island, Lamina Air Flow Unit),

• Hematopoietic Growth Factore (G-CSF, GM-CSF, Stem Cell Transplants)

肿瘤化学治疗中值 得 注 意 的 事 项

Precaution in Cancer Chemotherapy

• 1. 全面评估患者的病情– 有机结合各种治疗手段 (Multi-Modality

treatment)

• 2. 每一患者均有具体的治疗目标 :

– 根治性化疗 (Curative chemotherapy)

– 姑息性化疗 :• 延长寿命 (Palliative chemotherapy)• 缓解症状

– Palliative Care?

• 3. 权衡利弊– Toxicity– Benefit vs Risk– Cost

• 4. 尽量使用标准治疗方案 : ( Standard Protocol)– 经 Clinical Study 证实

• 密切观察 ,防止及处理不良反应 (Adverse effects)

Cancer Chemotherapy: New Advances• 1. Hi Dose CT/Stem Cell Transplantation• 2. New Anticancer Drugs

– Taxanes: TAXOL, TAXOTERE– Topoisomerase I Inhibitor:– CPT-10, CPT-11, TOPOTECAN– Gemcitabine– Oxaliplatin, Lobaplatin

• New Theraputic Targets– e.g. Anti-angioclonal(Angiostatin, Endostatin) – Monoclonal Antibody: Herceptin For Breast Cancer– (Her 2 neu over expression)– Gene therapy