Chapter 27 chemotherapy side effects dr lms

general oncology from devita presentation

1. CHEMOTHERAPY SIDE EFFECTS

2. Era of modern chemotherapy began in early 1940s Goodman and Gilman first administered nitrogen mustard to patients with lymphoma nitrogen mustard was developed as a war gas during (world war I) rather than as a medicine toxic effects on the lymphatic system led to clinical trials History of Chemotherapy

3. G 1 phase: cell prepares for DNA synthesis S phase: cell generates complete copy of genetic material G 2 phase: cell prepares for mitosis M phase: replicated DNA is condensed and segregated into chromosomes G phase: resting state The Cell Cycle

4. Cell cycle phase – specific agents with major activity in a particular phase of cell cycle schedule dependent Cell cycle phase – nonspecific agents with significant activity in multiple phases dose dependent Chemotherapy

5. Alkylating agents nitrogen mustards thiotepa , busulfan nitrosoureas , mitomycin procarbazine , dacarbazine Taxanes paclitaxel , docetaxel nab- paclitaxel Topoisomerase II inhibitors etoposide Platinum Complexes cisplatin , carboplatin oxaliplatin Chemotherapy Classes Anthracyclines doxorubicin, daunorubicin idarubicin , mitoxantrone Antimetabolites methotrexate purine antagonists pyrimidine antagonists Tubulin interactive agents vincristine , vinblastine Miscellaneous agents bleomycin asparaginase Hydroxyurea Targeted agents Hormonal agents Monoclonal antibodies

6. Most chemotherapy drugs are active in cells that are rapidly multiplying so besides their cytotoxic effects on cancerous cells they are also toxic to normal cells that are actively multiplying. Thus common toxicity of chemo agents are – Neutropenia , anemia, and thrombocytopenia ( myelosuppression or bone marrow suppression) Mucositis , diarrhea (GI toxicity) Nausea and vomiting Alopecia Sterility/Infertility (especially sterility in males) Side effects- The Concept

7. Side effects are dependent upon: Type of drug Dose that was given Frequency of administration Number of drugs in any particular regime Route of administration – drug concentration Patient’s co-morbidity Age ?

8. Activities of Daily Living (ADL) *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. **Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

9. Mature circulating haematopoeitic cells die off according to their respective life spans Deficient replacements from the marrow Clinical manifestations including leucopenia, thrombocytopenia, anemia Complications arise in severe cases Bone Marrow Suppression

10. Neutropenia is defined as an absolute neutrophil count (ANC) of <500 cells/mm 3 or an ANC that is expected to decrease to <500 cells/mm 3 during the next 48 hours. In neutropenic patients, fever (single oral temperature ≥38.3°C or sustained temp. ≥38°C for 1 hour) should be considered evidence of infection and treated accordingly. Febrile Neutropenia MASCC Score Treatment :- G-CSF or GM-CSF support along with Antibiotics and antifungal.

11. Defined as a platelet count <100 3 / μl (CTCAE) Complication- hemorrhage The risk of spontaneous bleeding including intracranial hemorrhage is increased when the platelet count drops to <10 3 / μ l. If the platelet count is <100 3 / μl at the beginning of a new cycle, the chemotherapy is delayed and the successive dose of treatment is decreased. Drugs that affect the early hematopoietic progenitors, such as the nitrosureas , mitomycin C, busulfan , and melphalan  delayed and cumulative thrombocytopenia New biologic agents- lenalidomide Thrombocytopenia

12. Causes- Antiangiogenic therapy ( bevacizumab , sunitinib , sorafenib ) Immunomodulatory agents (thalidomide- or lenalidomide -based combination regimens) Hormonal therapy agents (e.g., tamoxifen ) Erythropoiesis -stimulating agents Central venous access devices Transfusions Patients with cancer have a 3-fold higher risk of recurrent VTE and 2-fold higher risk of anticoagulant-related bleeding compared with patients without cancer. CLOT trial- LMWH is the preferred treatment for initial and long-term treatment compared with UFH and vitamin K antagonists (VKA). Thrombosis

13. Acute CINV- within 24hrs after chemotherapy Delayed CINV- more than 24hrs after chemo eg .- cisplatin , carboplatin , anthracyclines cyclophosphamide Anticipatory Nausea and vomiting- occur as the result of a conditioned response to prior episodes of CINV Chemotherapy Induced Nausea & Vomiting (CINV)

14. Commonly with Adriamycin , epirubicin All hair follicles Educate and reassure that hair will growback (about 3 – 5 month post chemo ) ALOPECIA (Hair Loss)

15. Commonly seen with 5-FU, Adriamycin , Cisplatin Ulcer Burning Sensation Pain Good oral hygiene Cryotherapy (ice chips) Good diet control Analgesics Antibiotics & Antifungals as required Oral Complications- Mucositis

16. Commonly with- 5-FU, capecitabine , and irinotecan (acute cholinergic properties) Targeted thearpy - bortezomib , erlotinib , gefitinib , sorafanib , sunitinib , imatininib , temsirolimus , everolimus . Dose-related adverse effect Multifactorial process whereby acute damage to the intestinal mucosa (loss of intestinal epithelium, superficial necrosis & inflammation) causes an imbalance between absorption and secretion in the small bowel. Neutropenic enterocolitis - myeloablative therapies Diarrhea

17. Constipation Dietary Management – fiber-rich foods such as bran, fruits,vegetables and nuts Prune juice is commonly used to relieve constipation Increase fluid intake Increase physical activities Laxatives Bulk Laxatives Osmotic Laxatives Polyethylene Glycol Lactulose Magnesium and Sulfate Salts Stimulant Laxatives Anthranoid Laxatives- senna Polyphenolic ( Diphenylmethane ) Detergents/Stool Softeners Liquid Paraffin Opioid Antagonists for Opioid induced Constipation- Methylnaltrexone is a quaternary derivative of naltrexone Enemas and Suppositories Managing Fecal Impaction - digital evacuation

18. Pulmonary toxicity Other drugs causing pulmonary toxicity- Antimetabolites - Methotrexate , gemcitabine , fludrabine Taxane - Docetaxel , paclitaxel TKI- EGFR inhibitors ( gefitinib , erlotinib ), Kit/BCR-ABL inhibitors ( imatinib , dasatinib ) Myeloma drugs- bortezomib , thalidomide, lenalidomide mTOR inhibitor- sirolimus , everolimus , temsirolimus Monoclonal Ab’s - VEGF inhibitor ( Bevacizumab ) EGFR inhibitor ( trastuzumab ) Immunotherapy- Nivolumab , Iplimumab

19. Anthracyclines - Reversible acute cardiotoxicity and delayed irreversible dilated cardiomyopathy Trastuzumab - cardiomyopathy 5-Fluorouracil (5-FU)- angina, atrial / ventricular arrhythmias, MI & cardiogenic shock Cyclophosphamide - acute myopericarditis associated with high-dose therapy and more commonly, acute or subacute CHF (reversible) Ifosfamide - Nonischemic cardiomyopathy (NICM) Paclitaxel - multiple: asymptomatic bradycardia & life threatening atrial and/or ventricular rhythm disturbances and/or conduction abnormalities Bevacizumab - A recent US FDA black box warning was placed on bevacizumab after an increase in risk of MI, angina, and heart disease Rituximab - no long-term cardiac toxicity; however, arrhythmias with cardiac death have been reported Cardiac toxicity

20. Taxanes , Platinum group Tingling, burning, weakness or numbness Shaking or trembling Difficulty in picking up objects, writing, buttoning clothes Advice to patients Be careful with sharp objects Avoid exposure to cold Wear shoes / sandals with rubber soles PERIPHERAL NEUROPATHY

21. Gonadal dysfunction (MALE)

22. Gonadal dysfunction (FEMALE)

23. VESICANTS- Are drugs that can cause tissue necrosis, pain and tissue sloughing at the site of extravasation . IRRITANTS- Are drugs that can cause aching, tightness, phlebitis with or without inflamation Extravasation

24. Leukemias secondary to chemotherapy agents have poor prognosis. Secondary to alkylating agents:- Most often occur after 5 – 7 years Often have MDS preceding leukemia Frequently FAB class M1 or M2 Alterations of chromosomes 5 and/or 7 in 60% – 90% cases Secondary to topo II inhibitors:- Diagnosed 2 -3 yrs after tx Most often FAB class M4 or M5 Frequent translocation of chromosome 11 (11q23) t(11;19)(q23;p13) Secondary Leukemias

25. Neurologic CNS : cytarabine , methotrexate , ifosfamide Peripheral: paclitaxel , oxaliplatin , vincristine Gastrointestinal Nausea and vomiting: cisplatin , doxorubicin, cyclophosphamide Mucositis : methotrexate , melphalan , etoposide , 5-FU Pulmonary- Methotrexate , bleomycin Cardiovascular- Anthracyclines , trastuzumab , 5 FU, cyclophosph Hepatic- busulfan Metabolic- Ifosfamide , cisplatin Renal Hemorrhagic cystitis: cyclophosphamide , ifosfamide Renal failure: cisplatin Chemotherapy side effects at a glance

26. Dermatologic Hand-foot syndrome: 5-FU, capecitabine , cytarabine Immune System Immunosuppression : fludarabine , cyclophosphamide , steroids Hypersensitivity: paclitaxel , asparaginase , bleomycin Miscellaneous Toxicity Asparaginase Coagulation disorders Hyperlipidemia Hyperglycemia Pancreatitis Etoposide - Hypotension, flushing (infusion-related) Irinotecan - Acute and delayed diarrhea (SN-38 metabolite) Chemotherapy side effects at a glance (contd.)

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