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Medical Pharmacology:  Chemotherapy Adverse Effects

 

  • Pyrimidine-analog antimetabolites:

    • Fluorouracil (5-FU)

      • Schedule-dependent toxicity

      • Bolus infusion: mainly bone marrow suppression

      • Continuous infusion: GI toxicity

      • Myocardial ischemic syndrome (uncommon)

      • Reversible neurological effects:

        • Headaches

        • Ataxia

        • Somnolence

      • Dermatologic (common):

        • Dermatitis

        • Skin atrophy

        • Hyperpigmentation

    •  Cytarabine (ARA-C)

      • Continuous infusion: significant myelosuppression

      • GI toxicity (including oral mucositis)

      • High-dose protocols: cholestatic jaundice; cerebral/cerebellar toxicity

      • Neurotoxicity (increased risk with age > 40; diminished renal function

      • Conjunctivitis: (preventable by ophthalmic corticosteroids)

    • Gemcitabine  (Gemzar):

      • Myelosuppression (dose limiting)

      • Lethargy; malaise

    Purine Analog antimetabolites:

    • Fludarabine (Fludara)

      • Reversible, usually mild, neurotoxicity

      • Myelosuppression

      • Immunosuppression (opportunistic infection in some patients)

    •  Cladribine (Leustatin)

      • Myelosuppression

      • Immunosuppression

      • GI toxicity (mild)

    •  Pentostatin (Nipent)

      • Immunosuppression

      • Myelosuppression

      • Renal dysfunction

      • CNS toxicity; lever toxicity

    • 6-mercaptopurine (6MP)

      • Patients receiving allopurinol -- 75% reduction mercaptopurine does (elimination depends on xanthine oxidase activity, which is inhibited by allopurinol)

      • Cholestatic jaundice

      • Myelosuppression

      • Mild gastrointestinal effects

    • 6-thioguanine (6-TG):

      • Cholestatic jaundice (more common with 6-mercaptopurine

      • Myelosuppression

      • Gastrointestinal toxicity (mild)

    Other Antimetabolites:

    • Methotrexate:

      • Severe gastrointestinal toxicity}avoided by administration of leucovorin

      • Significant bone marrow hypoplasia}avoided by administration of leucovorin

      • methotrexate may cumulative in fluid spaces (pleural effusions or ascites) -- may lead to severe toxicities as the drug elimination is prolonged.

      • Very high-dose methotrexate:

        • Acute renal injury (may be prevented by hydration and urine alkalinization)

        • Normal renal function is required for methotrexate elimination.

      • Liver toxicity

      • Idiosyncratic pneumonitis

    • Hydroxyurea (Hydrea):

      • Leukopenia (reversible upon discontinuation of drug)

      • Mild GI toxicity

      • Mild dermatologic changes with prolonged therapy

    Plant Alkaloids:

    • Vincristine (Oncovin):

      • Neurotoxicity -- dose limiting

        • Peripheral sensory neuropathy and/or autonomic neuropathy

        • Non-myelosuppressive

    • Vinblastine (Velban):

      • Dose limiting bone marrow hypoplasia (also seen with vinorelbine)

      • Significant neurotoxicity less frequently observed with vinblastine or vinorelbine than with vincristine)

    • Paclitaxel (Taxol)/docetaxel (Taxotere)

      • Infusion hypersensitivity (infusion vehicle may contribute)-- preventable by glucocorticoids.

      • Paclitaxel:

        • Bradyarrhythmias (A-V blockade)

        • Chest pain (atypical)

      • Myelosuppression: dose limiting

      • Peripheral neuropathy --common

      • Alopecia-- common

    Topoisomerase inhibitors:

    • Etoposide (VP-16,VePe-sid)/teniposide (Vumon)

      • Leukopenia: dose limiting

      • IV administration:

        • Hypotension

        • Fever

        • Bronchus spasm

        • Anaphylaxis

    • Anthracyclines and related compounds (doxorubicin (Adriamycin), daunorubicin (DaunoXome), idarubicin (Idamycin)) 

      • Myelosuppression

      • GI toxicity

      • Severe vesicants (blistering, tissue necrosis at injection site)

      • Long-term administration: limited by cumulative dose-dependent myocardial toxicity

      • Irreversible cardiomyopathy: significant risk with cumulative doses > 500 milligrams/m^2

        • concurrent cyclophosphamide administration or radiation therapy may lower acceptable cumulative dose.

      • Dactinomycin (Cosmegen):

        • Limited clinical use

        • Myelosuppression

    • Anthracenedione (mitoxantrone (Novantrone))

      • Cardiotoxicity

      • Significant myelosuppression

    Alkylating agents:

    • Depression in spermatogenesis

    • Depression in oogenesis

    • Mutagenic

    • Carcinogenic

    • Secondary leukemias

      • Patients receiving alkylating agents for treatment of Hodgkin's or non-Hodgkin's lymphoma:

        • 2% incidence of secondary myeloid leukemia (further increased incidence by addition of radiation therapy)

        • Not all alkylating agents equally leukemogenic

          • Melphalan: higher incidence compared to cyclophosphamide (in treating ovarian carcinoma)

      • Most common dose limiting toxicity: myelosuppression

    • Cyclophosphamide (Cytoxan):

      • Hemorrhagic cystitis (acrolein metabolite)

        • Prevented by adequate hydration and through the use of the bladder protectant, mesna

      • Chronic bladder inflammation

      • Antidiuretic effect (action on distal tubule)

      • Immunosuppression (myelosuppressive)

      • Acute myocardial necrosis (rare)

    • Ifosfamide (Ifex):

      • More urotoxic then cyclophosphamide (Cytoxan) (commonly administered with mesna)

      • Less myelosuppressive than cyclophosphamide

      • Neurotoxicity: reversible change in mental status.

    • Melphalan (Alkeran):

      • Especially leukemogenic

      • Pulmonary fibrosis (rare)

    • Busulfan (Myleran)

      • Myeloid stem cell toxicity

      • Bone marrow hypoplasia

      • Interstitial pneumonitis (rare)

      • Progressive pulmonary fibrosis (rare)

    • Mechlorethamine (Mustargen):

      • Severe vesicant (blistering)

    • Chlorambucil (Leukeran)--structurally similar to mechlorethamine, generally well tolerated

    • Thiotepa -Limited clinical use

    • Nitrosoureas (carmustine {BCNU}; lomustine {CCNU})

      • Delayed, cumulative myelosuppression

      • Increase in hepatic enzyme levels (moderate, reversible)

      • Prolonged treatment: progressive renal insufficiency

      • Leukemogenic

    • Platinum agents: Cisplatin (Platinol) and Carboplatin (Paraplatin) (not true alkylating agents, but do cause DNA cross-linking):

      •  Cisplatin (Platinol): Renal toxicity {toxic to proximal and distal renal tubule epithelial cells}

        • Adequate hydration and the use of high-ceiling diuretics (furosemide) or osmotic diuretics (mannitol) decrease likelihood of Nephrotoxicity

        • Nausea

        • Vomiting

        • Sensory neuropathy

        • High-frequency hearing loss -- not uncommon

        • Mild myelosuppression

      •   Carboplatin  (Paraplatin):  

        • Less nephrotoxic then cisplatin

        • Less ototoxic than cisplatin

        • Less nausea and vomiting than cisplatin

        • More myelosuppressive than cisplatin

    Antitumor antibiotics:

    • Bleomycin  (Blenoxane):

      • Pulmonary toxicity: chronic interstitial pneumonitis (most serious toxicity)

      • Test does required -- bleomycin infusion may cause hypersensitivity reactions

      • Little myelosuppressive effect

    • Mitomycin  (Mutamycin):

      • Delayed myelosuppression

      • May produce progressive renal failure-microangiopathic anemia (hemolytic-uremic syndrome)

    Other drugs:

    • Dacarbazine  (DTIC):

      • Some myelosuppression

      • Nausea/vomiting (may be severe)

    • Procarbazine  (Matulane):

      • Peripheral sensory neuropathy

      • Mood and mental status changes

      • Nausea/vomiting (may be severe)

    • L- asparaginase  (El-spar):

      • Hypersensitivity reactions; anaphylaxis

      • Hepatotoxicity-- occasional

      • Pancreatitis-- occasional

      • Thromboses-- occasional

       

Slapak, C.A., and Kufe, D.W. Principles of Cancer Therapy : In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 523-537.
 

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