35 Adverse effects of anticancer drugs (Antimetabolites agents, Alkylating agents, Antimicrotubule agents, Miscellaneous agents, Immune therapies and Biologically directed therapies ) 1
1- Nausea and vomiting Drugs causing nausea and vomiting Highly emetogenic Alkylating agents (Mechlorethamine, Carmustine, Dacarbazine, Cisplatin). 2
moderate emetogenic Alkylating agents (Ifosfamide, cyclophosphamide, carboplatin, oxaliplatin and Temozolamide) Antimetabolites agents (Cytarabine ) Miscellaneous agents (Mitomycin C) Immune therapies (Interleukin 2) Biologically directed therapies (Imatinib) 3
Antimicrotubule (Daunorubincin, Doxorubincin, epirubicin, idarubicin and irinotecan ) Mild emetogenic Antimetabolites agents (Fluorouracil, capecitabine, Gemcitabine, Azacitidine, Fludarabine,cladribine, mercaptopurine and methotrexate) 4
Antimicrotubule agents (Docetaxel, paclitaxel Vinblastine, vincristine vinorelbine,topotecan, Etoposide, Mitoxantrone) Alkylating agents (Busulfan, chlorambucil and Procarbazine) Miscellaneous agents (Arsenic trioxide, Asparaginase, Bleomycin and hydroxyurea) Biologically directed therapies (Bexarotene, bortezomib, Gefitinib, tretinoin and Rituximab) 5
Various combinations of the following classes of medications are used for treatment nausea and vomiting Serotonin receptor antagonists (5- HT3) ( odansetron) Dopamine receptor antagonists (D2) (metoclopramide) NK- 1 Receptor Antagonists ( Aprepitant) Systemic Corticosteroids (dexmethasone) Cannabinoid receptor agonist ( Dronabinol) 6
2- Myelosuppression Manifestations include low WBC especially neutrophil, platelets and erythrocytes. Drugs causing myelosuppression Antimetabolites agents Antimicrotubule agents except estramustine and vincristine. Alkylating agents except oxaliplatin and cisplatin Miscellaneous agents/ Mitomycin C Immune therapy Biologically directed therapies molecular targets/ Bortezomib Monoclonal antibodies/ Alemtuzumab and Gemtuzumab 7
Anemia The incidence of anemia depends on several factors, including the type and duration of therapy and the type and stage of the underlying malignancy. Multiple conditions are known to cause anemia in cancer patients including chronic gastrointestinal blood loss, nutrient deficiency, chemotherapy and radiation, bone marrow invasion by the tumor, hemolysis, renal dysfunction and anemia of chronic disease. Anemia in cancer patients treated by erythropoietic therapy (epoetin alfa and darbepoetin alfa). 8
Neutropenia When the Absolute neutrophil count (ANC) falls below 500/ mm3, infection risk increases. The diagnosis of infection in the neutropenia patient is complicated by the lack of WBCs. Infection in cancer patient can be prevented by Colonystimulating factors (CSFs) Granulocyte Colony- stimulating factors ( G-CSF) ( filgrastim) ( pegfilgrastim) Granulocyte macrophage Colony- stimulating factors ( GM- CSF) ( sargramostim) The side effects of G-CSFs is bone pain, increase in lactate dehydrogenase, alkaline phosphatase and uric acid levels. 9
The side effects of GM-CSF include constitutional symptoms, such as low grade fever, myalgia, arthralgias, lethargy and mild headache. GM-CSF may also increase in liver transaminases. At higher doses of GM-CSFs pleural and pericardial effusions, capillary link syndrome and thrombus formation may occur. Both G-CSF and GM-CSF may produce mild erythema at subcutaneous injection sites, as well as generalized maculopapular rash with either subcutaneous or intravenous administration. 10
Thrombocytopenia Chemotherapy induced thrombocytopenia puts the patient at risk for significant bleeding. Platelet transfusion is indicated for Patients with a platelet count of < 10000/mm3. Patients with lesser degrees of thrombocytopenia with sign and symptoms of hemorrhage. Patients with thrombocytopenia who must undergo surgical procedure. 11
Oprelvekin ( inteleukine 11) is indicated for Patients with nonmyeloid malignancies who experienced significant thrombocytopenia with a prior cycle of chemotherapy. Patients with high risk for severe thrombocytopenia after chemotherapy. Side effects of oprelvekin include fluid retention and cardiac toxicity, especially tachycardia and atrial fibrillation and flutter. 12
3- Alopecia Alopecia from chemotherapy is usually temporary. Loss of hair is not limited to the scalp; any area of the body may be affected. Cryotherapy ( local application of ice ) and scalp tourniquet have been investigated as methods of preventing alopecia. These techniques are not uniformly effective and contraindicated in patients with cancers that may metastasize to the scalp, such as leukemia and lymphoma. 13
Drugs causing alopecia Antimetabolites (cytarabine). Antimicrotubule agents (paclitaxel, docetaxel, irinotecan, etoposide, daunorubicin, doxorubicin, idarubicin and mitoxantrone) Miscellaneous agents (Bleomycin) Alkylating agents (Ifosfamide, Cyclophosphamide) 14
4- Mucositis The gastrointestinal mucosa is composed of epithelial cells with a high mitotic index and rapid turnover rate, making it a common site of chemotherapy induced toxicity. The inflammation, or mucositis, can lead to painful ulceration, local infection, and inability to eat, drink, or swallow. Patients at high risk for this toxicity include ( Those with poor dentition, high dose chemotherapy, or radiation therapy involving oropharynx). 15
The use of ice ( oral cryotherapy) may decrease the risk for mucositis by decreasing drug delivery to the oral mucosa. Keratinocyte growth factor (palifermin) are used for prevention of chemotherapy induced mucositis. When mucositis has developed, treatment mainly supportive, including use topical or systemic analgesics and oral hygiene( including the rinses ( chlorhexidine)). Sever cases of mucositis may lead to dehydration and require intravenous hydration. Local infection and reactivation of herpes simplex viruses are common in this patients. Suspicious lesions should be cultured, and appropriate antifungal and/ or antiviral therapy should be added. 16
Mucosal damage can occur at any point along the entire length of the GI tract. In the lower portion of the GI tract, this damage is usually manifested as diarrhea and abdominal pain. Support with IV fluids and electrolyte supplementation should be initiated in sever case. And also can be treated with antispasmodics such as loperaminde. The somatostatin analog octriotide has been used to treat sever cases of chemotherapy induced diarrhea. 17
Drugs causing mucositis Antimetabolites agents (Fluorouracil, capecitabine, cytarabine, Fludarabine, methotrexate and pemetrexed) Antimicrotubule agents (paclitaxel, irinotecan, toptecan,etoposide, daunorubicin, doxorubicin, idarubicin, mitoxantrone and Vinblastine). Miscellaneous agents (Bleomycin) Alkylating agents (oxaliplatin,procarbazine) 18
Immune therapy (interleukin-2) Biologically directed therapies (bortezomib,gefitinb, imatinib, tretinoin,cetuximab and tositumomab). 19
5- Flu-like syndrome with fever and arthralgias Antimetabolites agents (Cytarabine Aand Gemcitabine ) Miscellaneous agents (Bleomycin) Immune therapies (interferon alfa and interleukin-2) Premedication and scheduled dosing with acetaminophen or an NSAID may alleviate flu- like symptoms. 6- Fever Antimetabolites agents (Azacytidine) Biologically directed therapies (Bexarotene, Bortezomib, Gefitinib, Tretinoin, Alemtuzumab). 20
7- Rash Antimicrotubule agents(docetaxel) Antimetabolites agents (Fluorouracil, Cytarabine, Gemcitabine, 6- Mercaptopurine, Pemetrexed) Miscellaneous agents (Bleomycin, Arsenic trioxide, Asparaginase) Immune therapies (interleukin-2) Biologically directed therapies (imatinib, Alemtuzumab and Tositumomab ) 21
8- Hypersensitivity reaction Antimicrotubule agents ( paclitaxel and Docetaxel) Alkylating agents (carboplatin and oxaliplatin) Miscellaneous agents (Bleomycin and Asparaginase) Biologically directed therapies (cetuximab, rituximab, Tositumomab, gemtuzumab ozogamicin, ibrotumomab and trastuzumab) Premedicate with acetaminophen, diphenhydramine with or without dexamethasone to prevent hypersensitivity reactions. 22
9- Infertility High rates of fertility deficits and sexual dysfunction have been noted for both men and women. In men the antitumor drugs have been shown to produce severe oligospermia or azoospermia as well as infertility. Important factors for infertility in men include age, total dose, duration of therapy, and type of drug. In women, toxic effects on the ovaries result clinically in amenorrhea, vaginal epithelia atrophy, and menopausal symptom. Drugs causing infertility Alkylating agents (cycophosphamide, mechlorethamine, procarbazine, chlorambucil) 23
10- Secondary malignancies Secondary cancers induced by chemotherapy and radiation are a serious long term complication. acute nonlymphocytic leukemia or myelodysplastic syndrome has been reported following successful treatment of hodgkin lymphoma, acute leukemias, nonhodgkins lymphomas, multiple myeloma, breast cancer, and advanced ovarian cancer. Solid tumors as secondary malignancies occur more commonly after treatment with radiation than with chemotherapy. 24
Drugs causing secondary malignancies Miscellaneous agents (hydroxyurea). Alkylating agents (cyclophosphamide, mechlorethamine, procarbazine) 11- liver toxicity 1- elevation liver function tests Antimetabolites ( gemcitabine), Antimicrotubule agents ( irinotecan and topotecan) Alkylating agents ( chlorambucil) Immune therapy (interferon alfa) Biologically-directed therapies ( bexarotene, imatinib,tretinoin and Gemtuzumab) 2- jaundice and hyperbilirubinemia Antimetabolites ( 6- mercaptopurine) 3- cirrhosis and portal fibrosis Antimetabolites (methotrexate) 25
4- hepatic veno-occlusive disease Alkylating agents (busulfan) Biologically-directed therapies ( Gemtuzumab ) Hepatic veno-occlusive disease is treated by defibrotide. 26
12- Nephrotoxicity Alkylating agents ( carmustine, cisplatin, ifosfamide) Immune therapy (interleukin-2) Antimetabolites (methotrexate). Amifostine is used to decrease risk of nephrotoxicity of chemotherapy. 27
13- hemorrhagic cystitis (HC) Drug causing hemorrhagic cystitis Alkylating agents (cyclophosphamide and ifosfamide). For prevention HC hydration and 2- mercaptoethane sulfonate ( Mesna) are needed. 28
14- Neurotoxicity 1- Cerebellar toxicity antimetabolites (cytarabine) 2- Peripheral neuropathy Antimicrotubules (vincristine, vinblastine, vinorelbine, paclitaxel and docetaxel) Alkylating agents (cisplatin, oxaliplatin and procarbazine ) Biologically-directed therapies (bortezomib) Glutathione, magnesium, calcium and vitamin E being used for prevention of neuropathies. 3- seizures Alkylating agents (busulfan) 4- Confusion, somnolence and disorientation Alkylating agents (ifosfamide ) Miscellaneous agents ( interleukin-2) 29
15- pulmonary toxicity Drug causing pulmonary toxicity 1- Dyspnea Antimetabolites ( Gemcitabine, Azacitidine) 2- Pulmonary fibrosis Miscellaneous agents (bleomycin) Alkylating agents (busulfan, carmustine and chlorambucil) 3- Interstitial lung disease biologically-directed therapies (Gefitinib) Antimetabolites ( fludarabine) Alkylating agents (chlorambucil) 30
16- Cardiotoxicity Myocardial ischemic symptom ( flurouracil) Cardiac toxicity Antimicrotubules ( paclitaxel,daunorubicin, doxorubicin, idarubicin, mitoxatrone) Biologically-directed therapies(trastuzumab). Liposomal form of anthracene reduce risk od cardiotoxicity. And also can be reduced by use cardioprotective ( Dexrazoxane). 31
17- Tumor lysis syndrome Clinical characterized by rapid development of hyperuricemia; hyperkalemia; hyperphosphatemia, hypocalcemia and acute renal failure. Drugs causing tumor lysis syndrom Biologically-directed therapies(gemtuzumab and Rituximab) Antimetabolites(Cytarabine, fludarabine) Miscellaneous agents (Hydroxyurea) Hyperuricemia is treated by allopurinol or Rasburicase 32
18- Extravasation injury Vesicants are antineoplastic agents that may cause sever tissue damage if they escape from the vasculature. These agents include Antimicrotubule agents Anthracyclines ( Doxorubicin, Daunorubicin, Idarubicin and Epirubicin) Vinca alkaloids ( vinblastine, vincristine and vinorelbine), - - Taxanes ( Docetaxel and paclitaxel). Miscellaneous agents (mitomycin C) Alkylating agent (mechlorethamine) 33
For extravasation vesicants, one of the most important interventions is the application of ice packs to the affected area. One exception this rule is the vinca alkaloids, which are better managed with application of heat. Sodium thiosulfate is used to treat mechlorethamine extravasations and hyaluronidase can improve the outcome after extravasation of vinca alkaloids, etoposide, and taxanes. Topical application of dimethyl sulfoxide may be an effective method for managing anthracycline and mitomycin extravasations. 34