วัตถุประสงค์

1. 12. การรักษามะเร็งโดยเคมีบำบัด (Cancer Chemotherapy) วัตถุประสงค์ • สามารถอธิบายข้อแตกต่างของ Clinical trials แต่ละ Phase ได้ • สามารถอธิบายหลักการการรักษามะเร็งโดยเคมีบำบัด เนื้อหา 12.1 Introduction 12.2 Clinical Trials 12.3 Treatment Strategies 12.4 Pharmacologic principles : General mechanism of action

2. 12. Cancer Chemotherapy 12.1 Introduction • Several drugs and compounds are in use or in different stages of clinical trials. ----> only a few of these usually get approved for treatment of cancers • Antineoplastic agents are classified based on their mechanism (s) of action or by their origin. ----> antimetabolites, alkylating agents, anthracyclines and related intercalators, hormonal agents, microtubule targeting agents or plant alkaloids,DNA topoisomerase inhibitors, and miscellaneous agents. • To date, most anticancer drugs are nonselective in their mechanism of action and are directed at essential components or metabolic pathways that are crucial to both the malignant and normal cells. • Knowledge about the biology of tumors and the pharmacology of anticancer agents can improve the efficiency of chemotherapy.

3. 12.2 Clinical Trials • Clinical trials involving new drugs are commonly classified into four phases. • The drug-development process will normally proceed through all four phases over many years. • If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV are 'post-approval' studies. 12.2.1 Phase 1 Trials (Phase I) • They are usually small trials, recruiting anything up to about 30 patients, although often a lot less. • The trial may be open to people with any type of cancer. • When laboratory testing shows that a new treatment might help treat cancer, phase 1 trials are done to find out: • - The safe dose range                • - The side effects                • - How the body copes with the drug                • - If the treatment shrinks the cancer

4. Phase 1 trials aim to look at doses and side effects. • Phase 1 trials are important because they are the first step in finding new treatments for the future. 12.2.2 Phase 2 Trials (Phase II) • Not all treatments tested in a phase 1 trial make it to a phase 2 trial. • These trials may be done on people who all have same type of cancer, or with several different types of cancer. • Phase 2 trials aim to find out : - If the new treatment works well enough to test in a larger phase 3 trial. -Which types of cancer the treatment works for. - More about side effects and how to manage them. - More about the best dose to use. • Phase 2 trials are often larger than phase 1.  There may be up to 100 or so people taking part. • If the results of phase 2 trials show that a new treatment may be as good as existing treatment, or better, it then moves into phase 3.

5. 12.2.3 Phase 3 Trials (Phase III) • These trials compare new treatments with the best currently available treatment (the standard treatment). • These trials may compare: • - A completely new treatment with the standard treatment             • - Different doses or ways of giving a standard treatment             • - A new radiotherapy schedule with the standard one • Phase 3 trials usually involve many more patients than phase 1 or 2. • Sometimes phase 3 trials involve thousands of patients in many different hospitals and even different countries. • Phase 3 trials are usually randomised. This means the researchers put the people taking part into 2 groups at random. One group gets the new treatment and the other the standard treatment.

6. 12.2.4 Phase 4 Trials (Phase IV) • Phase 4 trials are done after a drug has been shown to work and has been granted a license. • These trials look at drugs that are already available for doctors to prescribe, rather than new drugs that are still being developed. • The main reasons pharmaceutical companies run phase 4 trials are to find out : • - More about the side effects and safety of the drug             • - What the long term risks and benefits are             • - How well the drug works when it’s used more widely than in clinical trials 12.3 Treatment Strategies • Three principles underlie the general approach to designing specific regimens for the treatment of cancer. 1) Drugs are more effective when used in combination. 2) Drugs are more effective at higher doses. 3) Drugs should be used in conjunction with local therapies such as surgery and radiation.

7. 12.3.1 Combination Chemotherapy • Anticancer drugs in general are more effective when used in combination. • It is desirable : 1) to avoid an overlap of major toxicities, mechanism of action, and resistance mechanism (s). 2) to administer most drugs at their maximum tolerated doses with minimum time intervals between such doses. • Combination chemotherapy may promote additive or possible synergism and decrease the emergence of resistance in early tumor cells. 12.3.2 Dose intensity/density • Dose intensity refers to the amount of drug administered per unit of time (i.e. mg per square meter per week). • The use of dose intensification in humans should always consider existing conditions in a patient. ----> organ dysfunction, prior toxicities, performance status, and other medical problems

8. 12.3.3 Adjuvant Chemotherapy • Adjuvant therapy refers to additional treatment, usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to occult disease. • Chemotherapy or Radiotherapy is commonly given as adjuvant treatment after surgery for a breast cancer. • Adjuvant chemotherapy and radiotherapy are often given following surgery for many types of cancer, including colon cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and some gynaecological cancers. • Neoadjuvant therapy, in contrast to adjuvant therapy, is given before the main treatment. For example, chemotherapy that is given before removal of a breast is considered neoadjuvant chemotherapy. • The most common reason for neoadjuvant therapy is to reduce the size of the tumor so as to facilitate more effective surgery.

9. 12.4 Pharmacologic principles : General mechanism of action • The mechanism of action of anticancer drugs is usually through the alteration of signaling pathways in cancer cells. ----> also affected in normal dividing cells • Many of the antimetabolites (e.g., 5-fluorouracil, methotrexate, 6-thioguanine) and alkylating agents (cisplatin, melphalan) require chemical or enzymatic activation intracellulary before cytotoxicity can be achieved. • Generally, drug has to be present and maintained at adequate concentration at its site of action. • To produce cytotoxicity, most anticancer drugs require uptake into the cell, except L-asparaginase that inhibits cell growth by depletion of circulating L-asparagine. • There are a number of mechanisms by which anticancer drugs result in cytotoxicity.

10. Alkylating agents and platinum compounds (Covalent DNA-binding drugs)

11. Alkylating agents and platinum compounds (Covalent DNA-binding drugs)

12. Alkylating agents and platinum compounds (Covalent DNA-binding drugs)

13. Antimetabolites - Pyrimidine analoques ---> Inhibits DNA/RNA Synthesis - Purine analoques ---> Inhibits DNA Synthesis ---> Inhibits purine Synthesis - Chelate analoques ---> Inhibits purine and thymidylate Synthesis

14. Anthracyclines and Related intercalators

15. Antimitotic antineoplastic agents (Antimicrotubular drugs)

16. Topoisomerase inhibitors