Principles of Chemotherapy PDF

(L5) PRINCIPLES OF CHEMOTHERAPY  LECTURE 05 PRINCIPLES OF CHEMOTHERAPY Cancer Chemotherapy Definition and principle  Treatment with drugs that kill cancer cells (or make the...

(L5) PRINCIPLES OF CHEMOTHERAPY  LECTURE 05 PRINCIPLES OF CHEMOTHERAPY Cancer Chemotherapy Definition and principle  Treatment with drugs that kill cancer cells (or make them less active) by interfering with tumor cells ability to grow and proliferate.  They attack tumors at the cellular level by interrupting processes or inhibiting substances necessary for cellular replication and life. Types ① Adjuvant chemotherapy ⑤ Maintenance chemotherapy ② Nea-adjuvant chemotherapy ⑥ Palliative chemotherapy ③ Radio sensitizer chemotherapy ⑦ Salvage chemotherapy ④ Induction chemotherapy 1 Adjuvant chemotherapy  Adjuvant chemotherapy is given to kill microscopic cells that may remains after a known tumor is removed by surgery lowering the chance of recurrence.  Childhood malignancies:  Respond best to a combination of Surgery + radiotherapy + chemotherapy  Such as: ① Retinoblastoma ② Wilms ③ Embryonal rhabdomyosarcoma  in adults with skeletal and STS of limbs:  Preoperative intra-arterial infusion of Adriamycin followed by radiation, surgical excision and postoperative Adriamycin has dramatically reduced incidence of pulmonary 2ry and improved recurrence – free survival Dr.Noaman Page 1  Medicine - Delta Semester (7) Principles of chemotherapy 2 Neo-adjuvant chemotherapy  Make distinction between the cancerous and healthy tissue easy.  This reduces the amount of healthy tissue removed during the actual surgical procedure.  For many cancer patients neo-adjuvant chemotherapy provides a faster recovery time and better mobility after surgery.  Some patients might not be suited for this type of therapy, especially if the side effects would render them unfit for surgery later. 3 Radio sensitizer 4 Induction chemotherapy  Chemotherapy is given to induce a remission.  It is usually part of a treatment for acute leukemia 5 Maintenance chemotherapy  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. 6 Palliative chemotherapy  Chemotherapy given to control symptoms or prolong life in a patient in whom cure is unlikely 7 Salvage chemotherapy  A potentially curative, high-dose, usually combination, regimen given in a patient who has failed or recurred following a different curative regimen Dr.Noaman Page 2  Medicine - Delta Semester (7) Principles of chemotherapy Cell Cycle Phase specific Agent ① Capecitabine S phase ② 5FU ③ Methotrexate ① Vinca Alkaloid M phase ② Taxanes G2 phase  Bleomycin G1 phase  Corticosteroids Goals of Chemotherapy ① To cure cancer with the fewest or least harmful side effects. ② To control cancer by keeping the cancer from spreading, slowing its growth and killing cancer cells that may have spread to other parts of the body away from the original tumor. ③ To relieve symptoms, such as pain, caused by the cancer and allow patients to live more comfortably Notes  The drugs may be used in the form of: ① Continuous suppressive therapy or ② Intermittent courses.  They are given as initial doses until marrow depression occurs then the dose is reduced or spaced out.  Dose is controlled by: ① Blood picture ② Physical signs. Dr.Noaman Page 3  Medicine - Delta Semester (7) Principles of chemotherapy Administration of chemotherapy ① Intra arterial perfusion:  With extracorporeal circulation for the infused part  Highly effective with low toxicity. ② Regional perfusion. ③ Systemic chemotherapy:  Systemic chemotherapy is administered through veins, muscles or mouth in which the drugs are passed within the bloodstream to reach the cancerous cells all throughout the patient's body. indications of Chemotherapy ① Breast cancer (Cancer of the breast and metastases) ② Tumors of the head and neck ③ Stomach carcinoma ④ Bladder carcinoma ⑤ Prostate carcinoma Tumors with good response ⑥ Ovarian carcinoma rates ⑦ Cholangiocellular carcinoma ⑧ Anal carcinoma ⑨ Hypernephroma ⑩ Thyroid carcinoma ⑪ Esophageal carcinoma ⑫ Carcinoid tumors ① Bronchial carcinoma ② Pancreatic carcinoma Tumors with moderate to ③ Hepatocellular carcinoma good response rates ④ Soft tissue sarcomas ⑤ Malignant melanoma ⑥ Carcinoma of the cervix Tumors with poor to ① Large bowel and rectal carcinoma moderate response rates ② Gall bladder carcinoma Dr.Noaman Page 4  Medicine - Delta Semester (7) Principles of chemotherapy Deployment of cytotoxic drugs 1 Continuous single agent chemotherapy ① Little value in modern cancer therapy ② Low response rate ③ Complete remission where infrequent ④ Kill small fractions of tumor cells ⑤ Potentiates the development of drug resistance 2 Cyclic chemotherapy ① Drugs are given in cyclic fashion ② Helps to prevent drug resistance ③ Prolong remission 3 Combination chemotherapy ① Superior to single drug chemotherapy ② Drugs should be active as single agent ③ Avoid drugs with similar toxicity ④ Use drugs with different mechanism of action ⑤ Use maximum therapeutic doses  Examples of combined chemotherapy:  MOPP:  CVP: ① Mustargen ① Cyclophosphamide 1 Lymphoma ② Oncovin ② Vincristine ③ Predinisone ③ Predinisone ④ Procrbazine ① Vincristine 2 Acute leukaemia ② Predinisone ③ 6- mercaptopurine Dr.Noaman Page 5  Medicine - Delta Semester (7) Principles of chemotherapy  CMF: Disseminated ① Cyclophosphamide 3 breast cancer ② Methotrexate ③ 5-FU  Triple regimen BEP: ① Bleomycin 4 Testicular tumor ② Etoposide ③ Platinum based agent  Advantages of combined chemotherapy: ① Chance of resistance is small since the tumor is exposed to a wider variety of agents. ② A maximal killing effect is achieved without undue toxicity. ③ Less opportunity for early emergence of a resistant cell population. ④ Obtaining a synergistic effect on the tumor by blocking multiple biosynthesis pathways. Pre-chemotherapy assessment ① Definitive diagnoses and accurate staging:  No room for therapeutic trial of chemotherapeutic agents. ② Detailed history. ③ Physical examination ④ Performance status ⑤ Investigations: hematological, biochemical, imaging and tumor markers. ⑥ Counseling ⑦ Optimization: blood and antibiotic as needed. Dr.Noaman Page 6  Medicine - Delta Semester (7) Principles of chemotherapy Response to Chemotherapy (according to WHO) Objective response → Means change in longest diameter of target lesion  Disappearance of all known disease confirmed at >4 1 Complete response (CR) weeks 2 Partial response (PR)  >50% decrease from baseline confirmed at >4 weeks  >25% increase in one or more lesion or appearance of 3 Progressive disease (PD) new lesions 4 Stable disease (SD)  Neither PR nor PD criteria met (no change) Resistance to therapy ① Cancer cells may learn to repair the DNA & protein damages induced by anticancer drugs ② Resistant clones of cancer cells may develop ③ Increase genetic instability as cancer grows. ④ Cellular hypoxia may cause resistance. ⑤ Decrease intracellular activation: as with 6-MP and 5-FU. ⑥ Increase intracellular breakdown: as with Cytosine arabinoside. ⑦ Bypass biochemical pathway: as with methotrexate, 6- MP, and Asparaginase. Dr.Noaman Page 7  Medicine - Delta Semester (7) Principles of chemotherapy Chemotherapy toxicity  Toxicity depends on many factors: ① Drug dosing and schedule ② Patient ③ Disease ④ Chemotherapy regimens: combine drugs have different toxicity profiles.  It may be classified into: Non specific Specific ① Skin lesions ⑥ Vomiting ② Hematological ⑦ Mucositis ① Cardiotoxicity ④ Nephrotoxicity ③ GIT ⑧ Superadded infection ② Pulmonary ⑤ Tumor lysis ④ Endocrinal ⑨ Ototoxicity ③ Bladder ⑥ Hepatotoxicity ⑤ Neurological ⑩ 2ry tumors 1 Infusion reactions  Very common with new monoclonal antibody agents i.e. Etiology RITUXIMAB  Infusion of these agents may take several hours ① Fever ③ Asthmatic like reactions C/P ② Hypotension ④ Pain ① Premedicate or treat with Dexamthasone. Management ② May have to stop infusion temporarily ③ If serious, may have to discontinue agent 2 Skin complications ① Alopecia ② Darkening of skin and nails noticed with 5FU ③ Hand foot syndrome: 5FU, Capecitabine and Cytarabine Dr.Noaman Page 8  Medicine - Delta Semester (7) Principles of chemotherapy 3 Hematological complications ① Anemia 1. Due to Bone marrow suppression. 2. Secondary to malignancy ② Leucopenia ③ Thrombocytopenia ④ Febrile neutropenia 4 GIT complications: ① Nausea and vomiting:  Drugs: 1. Cisplatin 2. Doxorubicin 3. Cyclophosphamide.  Most chemotherapeutic agents cause nausea through: 1. Stimulation of chemotherapeutic trigger zone. 2. Sight and smell of drug.  Types of Nausea 1. Anticipatory 2. Acute 3. Delayed ② Mucositis: 1. Methotrexate 2. melphalan 3. etoposide 4. 5-FU. ③ Sloughing of mucosa leading to diarrhea:  Very common  Approx 45%  Usually a few days and self-limiting. ④ GIT infection Dr.Noaman Page 9  Medicine - Delta Semester (7) Principles of chemotherapy 5 Oral complications  Occurs in approx. 40% of patients receiving chemotherapy. ① Loss of taste. ② Loss of appetite. ③ Simple oral mucositis. 6 Neurological complications  Drugs: ① Cytarabine 1 CNS ② Methotrexate ③ Ifosfamide  Confusion  Very common with: ① Vincristine ② Vinblastine ③ Cisplatin  Usually temporary. 2 Peripheral neuropathy  Symptoms:  Numbness and tingling in fingers and toes  Treatment:  May need to alter chemotherapeutic agents or doses. 7 Genitourinary complications ① Nephrotoxicity. ② Renal failure: cisplatin ③ Hemorrhagic cystitis: cyclophosphamide & ifosfamide. 8 Secondary leukemia  Leukemia secondary to chemotherapy agents have poor prognosis.  Secondary to alkylating agents: Most often occur after 5 - 7 years Dr.Noaman Page 10  Medicine - Delta Semester (7) Principles of chemotherapy 9 Immunological complications ① Immunosuppression: ② Hypersensitivity: 1. Fludarabine 1. Paclitaxel 2. Cyclophosphamide 2. Asparaginase 3. Steroids 3. Bleomycin Prevention and management of complications ① Relaxation. ② Varying foods & meals ③ Medications: 1 Nausea and vomiting 1. Prochlorperazine. 2. Metoclopramide. 3. Ondansetron (Zofran)-5HT3 antagonists 4. Dexamethasone 5. Lorazepam, Haloperidol ① Eprex 40,000 units sc weekly 2 Anaemia ② Aranesp: 150mcg sc weekly ③ Blood transfusion ① Nutrition supplements. ② Oral hygiene; soft tooth brushes. ③ Mouthwash. 3 Oral complications ④ Salt water gargles. ⑤ Topical analgesia as Xylocaine viscous, tantum ⑥ Systemic analgesia ⑦ Nystatin ① Colony stimulating factors 4 Immunosuppression ② BM transplantation ③ Broad spectrum antibiotics Dr.Noaman Page 11