PRINCIPLES OF CANCER CHEMOTHERAPY

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CANCER CHEMOTHERAPY:

CANCER CHEMOTHERAPY DR AROJURAYE S.A SURGERY DEPARTMENT ABUTH, SHIKA-ZARIA

OUTLINE:

OUTLINE Introduction Cell cycle Definition of terms Commonly used cytotoxic drugs Routes of administration Deployment of cytotoxic drugs Pre-chemotherapy assessment Response & Resistance to Chemo. Complications & Management Conclusion

Introduction:

Introduction Cancer chemotherapy is a branch of cancer treatment that involve the use of chemical agents to destroy cancer cells. Other modalities of cancer Rx include surgery, radiation, immune modulation, & marrow transplants.

Introduction:

Introduction The aim of cancer chemotherapy is to cure where possible and palliate where cure is impossible. The effective use of cancer chemotherapy requires an understanding of the principles of tumor biology, cellular kinetics, pharmacology, and drug resistance.

Cell Cycle:

Cell Cycle A constantly proliferating cell (normal or malignant) repeats a cycle of events that eventually end with cell division

Cell Cycle:

Cell Cycle The progression of a cell through this cycle is promoted by cycline dependent kinases which when complexed with cyclines drives the cell through cell cycle.

Cell Cycle:

Cell Cycle Generation time – The time taken by a cell to complete one cell cycle. Growth fraction – The fraction of cells in cycle that are proliferating at a given time. Tumour with high growth fractions & short generation times (clinically fast growing tumour) are more susceptible to chemotherapy.

Definition of terms:

Definition of terms Induction: chemotherapy given with the intent of inducing complete remission when initiating a curative regimen. usually applied to hematologic malignancies. Consolidation: Repetition of the induction regimen in a patient who has achieved a complete remission after induction, with the intent of increasing cure rate or prolonging remission.

Definition of terms:

Definition of terms Intensification: Chemotherapy after complete remission with higher doses of the same agents used for induction or with different agents at high doses with the intent of increasing cure rate or remission duration.

Definition of terms:

Definition of terms Maintenance: Long-term, low-dose, single or combination chemotherapy in a patient who has achieved a complete remission, with the intent of delaying the regrowth of residual tumor cells.

Definition of terms:

Definition of terms Adjuvant: A short course of high-dose, usually combination chemotherapy in a patient with no evidence of residual cancer after surgery or radiotherapy, given with the intent of destroying a low number of residual tumor cells. Neoadjuvant: Adjuvant chemotherapy given in the preoperative or perioperative period.

Definition of terms:

Definition of terms Palliative: Chemotherapy given to control symptoms or prolong life in a patient in whom cure is unlikely. Salvage: A potentially curative, high-dose, usually combination, regimen given in a patient who has failed or recurred following a different curative regimen.

Cytotoxic drugs:

Cytotoxic drugs Alkylating agents Examples: Cyclophosphamide, Chlorambucil, Mephalan They are highly reactive drugs that restrict the action of biological molecules such as proteins and DNA by binding to them They add alkyl groups to the electronegative groups in cancer cells

Cytotoxic drugs:

Cytotoxic drugs Antimetabolites Examples: Methotrexate, 5-FU, Cytosine arabinoside They masquerade as purines or pyrimidines & prevent these substances from becoming incorporated into DNA during the ‘s’ phase of the cell cycle. Act by inhibiting metabolic pathways usually of DNA synthesis, thus preventing replication & inducing cell death.

Cytotoxic drugs:

Cytotoxic drugs Plant Alkaloids Examples: Vincristine, Vinblastine, Taxanes (Paclitaxel, Docetaxel) They cause mitotic arrest by poisoning the spindles Mitotic spindles are vital for cell division

Cytotoxic drugs:

Cytotoxic drugs Antibiotics Example: Adriamycin, Epirubicin, Bleomycin Cause linkage of double strands of DNA & prevent replication

Cytotoxic drugs:

Cytotoxic drugs Podophyllotoxins Etoposide, Tenoposide They are plant derivatives They prevent the cell from entering the G1 and S phase of the cell cycle

Cytotoxic drugs:

Cytotoxic drugs Platinum compound Cisplatinum, Carboplatin, Oxaliplatin They are alkylating agents & they form cross-linking adducts, thus blocking DNA replication & transcription.

Hormonal therapy:

Hormonal therapy Anti-Estrogen: Tamoxifene, Raloxifene Aromatase inhibitors: Anatrozole,Letroxole Anti-testosterone: Finastride, blocks peripheral conversion of testosterone to dihydrotestosterone

Hormonal therapy:

Hormonal therapy GnRH agonist: Goserelin, produce paradoxical negative feedback effect followed by inhibition of the release of FSH & LH when given continuously. Steroids: Dexamethaxone, inhibit tumour growth, reduce inflammation & edema associated with it, prevent vomiting & cause regression of lymph node malignancies.

Mechanism of action in relation to cell cycle:

Mechanism of action in relation to cell cycle Cell cycle specific i. Phase specific - 5FU ii. Phase non-specific – Cyclophosphamide Cell cycle non-specific They act on all phases of cell cycle Example is corticosteroids

Mechanism of action in relation to cell cycle:

Mechanism of action in relation to cell cycle Cell cycle phase nonspecific agents have a linear dose response curve. Fraction of cells killed increases with drug dose. Cell cycle phase specific drugs have a plateau beyond which increased dose does not increase cell kill.

Cell Cycle Phase specific Agent:

Cell Cycle Phase specific Agent S-phase Capecitabine, 5FU, Methotrexate M-phase Vinca Alkaloid, Taxanes G2-phase Bleomycin G1-phase Corticosteroids

Chemoradiation:

Chemoradiation Integration of chemotherapy with radiotherapy. Drugs commonly used are 5FU and Cisplatin. Doxorubicin increases radiation toxicity to normal tissues and is thus not used in Chemoradiation.

Chemoradiation:

Chemoradiation Mechanisms of action include : Spatial cooperation deals with tumour that is spatially missed by the other. Simple addition of antitumor effects. Enhancement of tumour response. Protection of normal tissues.

Routes of Administration:

Routes of Administration Intravenous Oral Intrathecal / Intraventricular – used in meningeal metastasis. Intrapericardial – used in malignant pericardial effusion.

Routes of Administration:

Routes of Administration Intraperitoneal – used in ovarian cancer, colorectal cancer, mesothelioma. Intra-arterial – used in Liver cancer Isolated limb perfusion - used in MM

chemotherapy dosage:

chemotherapy dosage Based on BSA or weight BSA gives more accurate measure of fluid and tissue proportions Use normogram or BSA conversion calculator BSA (m²) = √ ht(cm) × w(kg) 3600

Deployment of cytotoxic drugs:

Deployment of cytotoxic drugs Continuous single agent chemotherapy Little value in modern cancer management - Low response rates. - Complete remissions were infrequent. - Kill small fractions of tumour cell - Potentiates the development of drug resistance

PowerPoint Presentation:

TREATMENT NUMBER OF CELLS KEY : Normal cells Tumour cells Time Effect of a Single Course of Cytotoxic Therapy on Tumour & Normal Tissues.

Deployment of cytotoxic drugs:

Deployment of cytotoxic drugs Cyclic Chemotherapy - Drugs are given in cyclic fashion. - Helps to prevent drug resistance. - Prolong remission.

PowerPoint Presentation:

TREATMENT NUMBER OF CELLS KEY : Normal cells Tumour cells Rx Rx Rx 3 2 1 Time Effect of Multiple Courses of Cytotoxic Therapy on Normal Tumour Cell population

Combination Chemotherapy:

Combination Chemotherapy Superior to single drug chemotherapy Considerations: Drug should be active as a single agent Avoid drugs with similar toxicity Use drugs with different mech. of actions Use maximum therapeutic doses

Pre-Chemotherapy Assessment:

Pre-Chemotherapy Assessment Essential Prerequisites : Definitive Diagnosis Accurate staging No room for ‘therapeutic trial’ of chemotherapeutic agents

Pre-Chemotherapy Assessment:

Pre-Chemotherapy Assessment Detailed Hx - Age Occupation Duration of symptoms Weight loss PMHx FSHx

Pre-Chemotherapy Assessment:

Pre-Chemotherapy Assessment Physical Examination Lymphadenopathy Organomegaly States of the heart & lungs Bone involvement Ht, Wt, BSA

Pre-Chemotherapy Assessment:

Pre-Chemotherapy Assessment Performance status Popular instrument used in oncology include Karnofsky performance index : Normal – 100% Death – 0% Eastern Cooperative Oncology Grp ECOG : 0 – Asymptomatic 5 - Death

Pre-Chemotherapy Assessment:

Pre-Chemotherapy Assessment Investigations Hematologic – FBC, ESR, BM biopsy Biochemical – LFT, RFT Imaging – CXR, USS, Bone scan, CT, MRI Tumour markers – gene products expressed in some cancers & may be used as diagnostic & monitoring tools. E.g. a-feto protein, PSA

Pre-Chemotherapy Assessment:

Pre-Chemotherapy Assessment Counseling Nature & stage Rx options Side effect Optimization Fluid & Electrolytes Blood if anaemic Antibiotics when indicated

Response to Chemotherapy:

Response to Chemotherapy WHO Objective response – Change in longest diameter of the target lesion.

Response to Chemotherapy:

Response to Chemotherapy Complete response (CR) Disappearance of all known disease, confirmed at ≥ 4 weeks ≥ 4 weeks Partial response (PR) ≥ 50% decrease from baseline, confirmed at ≥ 4weeks

Response to Chemotherapy:

Response to Chemotherapy Progressive disease (PD) ≥ 25% increase in one or more lesions or appearance of new lesions Stable disease (SD) Neither PR nor PD criteria met (no change)

Resistance to Chemotherapy:

Resistance to Chemotherapy Primary Resistance When the cancer does not respond to standard chemotherapy from the very first exposure. Acquired Resistance When the tumour initially responds to chemotherapy then becomes resistant.

Resistance to Chemotherapy:

Resistance to Chemotherapy Cancer cells may mutate & develop pathways that are independent of those blocked by cytotoxic drugs. Gene amplification may lead to overproduction of proteins that are blocked by anticancer drugs.

Resistance to Chemotherapy:

Resistance to Chemotherapy Cancer cells may develop mechanism that inactivate anticancer drugs. They may learn to repair the DNA & protein damages induced by anticancer drugs. Resistant clones of cancer cells may develop

Complications of Chemotherapy:

Complications of Chemotherapy Skin Alopecia Darkening of the skin & Nails Noticeable with 5FU Hematological - Anaemia, Leucopaenia, Thrombocytopenia - Almost all cytotoxic drugs

Complications of Chemotherapy:

Complications of Chemotherapy Gastrointestinal Nausea, Vomiting, Mucositis, GIT infection Almost all drugs Endocrine Infertility, Amenorrhea, Irregular menses Almost all drugs

Complications of Chemotherapy:

Complications of Chemotherapy Neurological Peripheral neuropathy Loss of interest Confusion Common with plant alkaloids

Complications of Chemotherapy:

Complications of Chemotherapy Others Ototoxicity – Platinum compounds Second tumors – Alkylating agents Cardiac toxicity – Anthracyclines Pulmonary toxicity – Bleomycin Bladder toxicity – Cyclophosphamide Nephrotoxicity – Platinum compound Tumour lysis syndrome

Prevention & Management of Complications:

Prevention & Management of Complications Nausea & Vomiting 5-HT3 receptor antagonist Ondasetron, Ganisetron Secondary tumors - Careful follow-up

Prevention & Management of Complications:

Prevention & Management of Complications Anaemia Erythropoietin Blood transfusion Immunosupression: Colony stimulating factor BM transplant Broad-spectrum antibiotics

Prevention & Management of Complications:

Prevention & Management of Complications Supportive Rx Leucovorin (folinic acid) is added when a very high dose Antimetabolites are given Colony stimulating factor & Erythropoietin can be used to supplement high dose chemotherapy

Conclusion:

Conclusion Chemotherapy is an important adjunct to surgery and radiotherapy in the management of cancer & It involves the use of cytotoxic drugs which exert their effects at different parts of the cell cycle. Cell kill is by first order kinetics.

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