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A. Overview of Side Effects [1,2]navigator

  1. Most Agents cause nausea and vomiting, mild to severe hair loss, fatigue
  2. Major Concerns with Common Agents
    1. Asparaginase: allergic reactions, pancreatitis, hypoproteinemia
    2. Bleomycin: lung toxicity leading to Interstitial Fibrosis
    3. Carboplatin: neurotoxicity > renal toxicity, little ototoxicity
    4. Cisplatin: renal failure, nausea / vomiting (acute and subacute), neurotoxicity
    5. Doxorubicin, daunorubicin, mitoxantrone: myocarditis and dilated cardiomyopathy [4]
    6. Ifosfamide: severe, reversible cardiotoxicity (low ejection fraction)
    7. Epirubicin has less cardiotoxicity than doxorubicin (Adriamycin) [5]
    8. 5-FU: stomatitis, bone marrow and CNS toxicity (due to lack of metabolizing enzyme)
    9. Methotrexate (MTX): Bone marrow and Hepatotoxicity, Lung Toxicity (reversible)
    10. Taxanes: myelosuppression, neuropathy, mucosal toxicity [6]
    11. Vinca Alakaloids (vincristine, vinblastine, navelbine): neuropathy, constipation
  3. Skin Toxicity
    1. Maculopapular Rash - Arabinoside C, MTX, hydroxyurea
    2. Hand-Foot Syndrome - palmar, plantar dysesthesia; capecitabine > 5FU, others [7]
    3. Recall Folliculitis - radiation to area, then doxorubicin / MTX (erythema, desquamation)
    4. Hyperpigmentation - bleomycin, busulfan, (doxorubicin nails only), hydroxyurea
    5. Mucositis - MTX, 5-FU, doxorubicin, etoposide, cyclophosphamide, navelbine, taxanes
    6. Hydroxyurea also causes cutaneous leg ulcerations, difficult to heal [7]
  4. Alopecia
    1. ~50% of all chemotherapies cause this
    2. Alkylating agents and taxanes are most common
    3. Daunorubicin, doxorubicin and AraC as well
  5. Bone Marrow Suppression
    1. Cell Cycle Specific Agents
    2. Includes AraC, MTX, Hydroxyurea, Topoisomerase inhibitors
    3. Cell count nadirs are rapidly reached post-chemotherapy
    4. Stem Cell Active Agents: Nitrosoureas, Busulfan. Nadir 14d post chemo
    5. Both Stem and Cycle Active Agents: doxorubicin, cyclophosphamide cause continuous nadirs
    6. CD4+ (particularly RO+/RA- memory type) T cells severely depleted by chemotherapy
    7. Persons <18 years replenish these cells more quickly than those >18 years of age
    8. Neutrophil count <500/µL associated with increased infection risk [8,9]
  6. Bone Marrow Support
    1. G-CSF or GM-CSF reduces duration of neutropenia
    2. Autologous stem cell reinfusion (± ex vivo growth) can improve marrow recovery
    3. Erythropoietin (EPO) to support erythropoiesis preferred over transfusion
    4. Target hemoglobin (Hb) no higher than 12gm/dL [52]
    5. Hb >12gm/dL associated with increased mortality rates [52]
    6. Platelet support with transfusions and now with Interleukin 11 (IL11, Neumega®) [10]
    7. IL11 may have additional efficacy in reducing mucositis; this is being investigated
    8. Multiple doses of recombinant human TPO (rhTPO) are very well tolerated
    9. Multiple doses of rhTPO prevented prolonged carboplatin-induced thrombocytopenia [11]
  7. Pulmonary Toxicity
    1. Bleomycin, busulfan and mitomycin C: idiopathic [12]
    2. MTX - delayed interstital, hpersensitivity pneumonitis with granuloma formation
    3. Evaluate with pulmonary function tests including DLCO
    4. Gallium scan often positive
    5. AraC causes a non-cardiogenic pulmonary edema
  8. Doxorubicin Induced Cardiac Disease [4,13]
    1. Initially causes myocarditis and/or pericarditis
    2. Free radical formation and damage to myocytes is most likely
    3. Arrhythmias may ensue
    4. With cumulative dosing (usually >500mg/m2), dilated cardiomyopathy occurs
    5. WIth cumulative doxorubicin 240-300mg/m2, cardiomyopathy occurs <1% [40]
    6. Safer as a constant infusion than as a bolus infusion
    7. Long term reduction in ejection fraction, very much dose related, increased in women
    8. Female sex and higher drug doses of doxorubicin (Adriamycin) correlate with development of dilated cardiomyopathy [14]
    9. Radioventriculogram (RVG) is superior to echocardiography for evaluting cardiac function
    10. Dexrazoxane (Zinecard®) is an iron chelating agent approved to reduce this toxicity [15]
    11. However, dexrazoxane increases risk of severe myelosuppression
    12. Dexrazoxane can reduce anthracycline induced cardiac damage without affecting antitumor activity when added to acute lymphoblastic lymphoma therapy [47]
    13. ß- blockers have been effective in treating (possibly reversing) cardiac toxicity [4]
  9. Caridac Disease from Other Agents [13]
    1. Mitoxantrone (adriamycin analog) also causes cardiomyopathy
    2. High risk in patients with heart disease, radiation therapy, hypertension, previous chemotherapy
    3. Ifosfamide can also cause an acute dilated cardiomyopathy
  10. Renal Toxicity
    1. Cisplatin is major cause of nephrotoxicity (much moreso than carboplatin)
    2. May cause a "Fanconi-like" Syndrome with K+ and HCO3- wasting (Type II RTA)
    3. Hemorrhagic Cystitis - cyclophosphamide and ifosfamide
    4. Tumor Lysis - release of intracellular materials
    5. Amifostine (Ethyol®) approved for renal protection with multidose platinums
    6. Amifostine appears to absorb free radicals and also protects against xerostomia
  11. Liver Toxicity
    1. AraC - associated usually with high Dose AraC (HiDaC)
    2. Methotrexate - usually reversible hepatitis
    3. Transplant patients - venoocclusive disease
  12. Neurological Toxicity
    1. Vincristine > Vinblastine: autonomic, peripheral neuropathies, constipation
    2. Vincristine - jaw pain (CN VI peripheral neuropathy ?)
    3. Taxanes (Paclitaxel and Docetaxel) - peripheral neuropathies (sensory and motor)
    4. Carboplatin > Cisplatin - ototoxicity, peripheral neuropathy
    5. AraC (Arabinosine C) causes an acute cerebellar syndrome (ataxia, dysequilibrium)
    6. Early signs of this syndrome: poor signature and decreased rapid alternating motion
    7. Methotrexate (intrathecal) - arachnoiditis with fever, paraplegia, encephalopathy
    8. Radiation (cranial) - may cause arachnoiditis
  13. Infection (see below)
  14. Secondary Tumors and Leukemias
    1. Alkylating agents are major causes 10-20 years after initial therapy [16]
    2. Risk of acute leukemia ~20X increased with alkylating agents [17]
    3. Topoisomerase II inhibitors
    4. Platinum based therapies for ovarian cancer carry 3-6X increased risk or leukemia [17]
    5. AML is most common secondary tumor
    6. MDS is frequently precursor
  15. Mucositis - see below
  16. Anaphylactic Reactions
    1. Asparaginase; may be decreased by Pegaspargase (Oncaspar®; PEG-conjugate)
    2. Paclitaxel
  17. Reproductive Effects
    1. Sperm Reduction - alkylating agents, doxorubicin, vinblastine, AraC, cisplatin
    2. Sperm counts and function are very sensitive to common combinations (such as MOPP)
    3. Testosterone may prevent cyclophosphamide induced azoospermia [18]
    4. Ovarian Dysfunction - cyclophosphamide (other alkylators), combination (such as MOPP)
    5. Oral contraceptive pills (OCPs) may prevent chemotherapy induced ovarian failure

B. Nausea and Vomiting [19,20] navigator

  1. Chemotherapy induced nausea and vomiting (CINV) is a major problem
  2. Emetogenic Potential of Standard Agents [19,43,45]
    1. High (>90%): cisplatin, carmustine, cytarabine, dacarbazine, mechlorethamine, streptozocin, high dose cyclophosphamide (CYC >1.5gm/m2)
    2. Moderate (30-90%): carboplatin, CYC (<1.5gm/m2), cytarabine (>1gm/m2), daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin, 5-FU
    3. Low (10-30%): bortezomib, cebuximab, cytarabine (<100mg/m2), docetaxel, gemcitabine, ixabepilone, lapatinib, methotrexate, mitomycin, mitoxantrone, paclitaxel, pemetrexed, temsirolimus, topotecan, trastuzumab
    4. Minimal (<10%): bevacizumab, bleomycin, fusulfan, cladribine, fludarabine, vinblastine, vincristine, vinorelbine
    5. No prophylaxis for minimal risk emetogenic potential recommended
    6. For low risk potential, dexamethasone or prochlorperazine prior to chemotherapy (none after)
    7. Prophylaxis strongly recommended before and after chemotherapy for moderate-high risk
    8. For anthracycline + CYC (moderate risk), 5-HT3 or NK1 antagonist or dexamethasone prior to chemotherapy; NK1 antagonist or dexamethasone for 1-2 days after chemotherapy
    9. For other moderate risk emetogenic chemotherapy: 5-HT3 antagonist or dexamethasone both prior to and after chemotherapy for 1-2 days
    10. For highly emetogenic chemotherapy, 5-HT3 antagonist + aprepitant (NK1 blocker) + dexamethasone should be used (similar to anthracycline+CYC) [45,46]
    11. Palanosetron is likely most effective 5-HT3 antagonist [45]
  3. Overview of Agents
    1. Serotonin 5-HT3 Receptor Antagonists - usually first line
    2. Combination with glucocorticoids (dexamethasone, high dose)
    3. Aprepritant (Emend®) - Neurokinin 1 Receptor (NK1) antagonist [21,45]
    4. Phenothiazines and Butyrphenones - now second line for most chemotherapy
    5. Anticholinergic Agents - less effective than others for chemotherapy
    6. Cannabinoids (dronabinol, nabilone) - active agent in marijuana; effective third line agent [51]
    7. Anticipatory nausea and vomiting occurs in many patients after initial chemotherapy
    8. Benzodiazepines are effective for anticipatory nausea and vomiting [40]
  4. Serotonin (5-hydroxytryptamine) Type 3 Receptor (5-HT3) Antagonists [22,23]
    1. Extremely effective for highly (and moderately) emetogenic chemoterhapy
    2. Ondansetron (Zofran®): 24-32mg bolus iv, or in 8-12mg divided doses, or continuous infusion, or 24mg po once 30 minutes before chemotherapy, or 8mg po bid
    3. Granisetron (Kytril®): 3mg IV, 10µg/kg IV q24°, 1mg po bid, or 2mg po before chemotherapy
    4. Palanosetron (Aloxi®): 0.25mg IV x 1 dose; very long half-life, covers up to 40 hours [46]
    5. Dolasetron (Anzemet®): 100mg iv or 1.8mg/kg once; oral 100mg once
    6. Tropisetron (Vavoban®) under development
    7. Also effective for post-chemotherapy residual and post-operative nausea and vomiting
    8. Dexamethasone (Decadron®) 20mg potentiates efficacy of these agents [22,24]
    9. Combinations of 5-HT3 antagonists with dexamethasone and aprepitant most effective for highly emetogenic chemotherapy, both acute and delayed [45,46]
    10. Main side effect is headache (~15%)
    11. Prophylaxis of emesis is more effective than treatment
  5. Glucocorticoids
    1. High dose glucocorticoid therapy is quite effective for nausea and vomiting treatment
    2. Dexamethasone PO or IV 20mg for highly- and 8mg for moderately-emetogenic chemotherapy
    3. After chemotherapy, 8mg qd for 2-4 days PO
    4. In patients who do not have acute emesis after initial dexamethasone + ondansetron, dexamethasone alone can control delayed nausea and vomiting []
    5. For moderately emetogenic regimens, glucocorticoids may be as effective as ondansetron
  6. NK1 Antagonists [21,45]
    1. Aprepitant (Emend®) approved for CINV with highly emetogenic chemotherapy
    2. Blocks neurokinin 1 (substance P) receptors and inhibits emetogenic response
    3. When combined with standard 5-HT3 antagonist+dexamethasone, substantially reduces acute and delayed emetic responses
    4. Dose 125mg po day 1, 80mg po qd days 2 and 3
    5. Fosaprepitant (Emend® for injection): 115mg IV prior to chemotherapy also available
  7. Phenothiazines
    1. May be used initially (but most physicians use serotonin antagonists)
    2. Mainly block dopamine receptors (D2, D3, some D4)
    3. Prochlorperazine (Compazine®) - 5-10mg po or iv, 25mg suppositories
    4. Perphanazine (Trilafon®)
    5. Thiethylperazine (Torecan®)
    6. Trimethobenzamide (Tigan®) - oral, suppositories, injectable
    7. Promethazine (Phenergan®)
  8. Metoclopramide (Reglan®)
    1. Appears to be more effective than standard phenothiazines
    2. Phenothiazine with excellent gastric emptying properties
    3. Dose 10-50mg iv or po q6-8 hours prn
  9. Butyrphenones
    1. Droperidol (Inapsine®) - highly effective, particularly with anesthetia induced nausea
    2. Haloperidol (Haldol®)
    3. Droperidone (Motilium®)
  10. Dronabinol (tetrahydrocannabinol, THC; Marinol®)
    1. Derived from marijuana
    2. Excellent anti-nausea agent but usually used third line
    3. Strong appetite stimulant as well
    4. Dose 5mg bid-tid prn orally
    5. Tachycardia, hypotension, memory problems, depression, vertigo, drowsiness
    6. Moderate abuse potential, schedule CIII
  11. Nabilone (Cesamet®)
    1. Oral active, synthetic cannabinoid
    2. Similar effects to marijuana
    3. High abuse potential, schedule CII
    4. Indicated for treatment of N/V associated with chemotherapy
    5. Dose 1-2mg po bid, maximum 6mg/day in 3 divided doses
    6. First dose is given 1-3 hours (and/or night) before chemotherapy
    7. Continue 2-3 doses/day during chemotherapy
    8. Drowsiness, vertigo, dry mouth, euphoria/dysphoria, ataxia, headache
    9. Tachycardia, hypotension, concentration difficulties, sleep disturbances
  12. Gabapentin (Neurontin®) [44]
    1. Gabapentin is an antiseizure agent with pain and other modulatory activities
    2. Small study in breast cancer patients receiving AC (doxorubicin and cyclophosphamide)
    3. Oral gabapentin 300mg po tid added to phenothiazines greatly reduced nausea, vomiting in these patients

C. Agents for Treatment of Bone Marrow Suppressionnavigator

  1. Leukovorin® (folinic acid)
    1. Folic acid derivative effective with 5-FU, methotrexate, others
    2. Reduces overall bone marrow suppression with these agents
    3. No apparent effect on efficacy
  2. Neutropenia Treatment / Prevention [8,9]
    1. Colony Stimulating Factors (CSFs)
    2. G-CSF (filgrastim) - especially in fever/neutropenic patients and in patients on Taxol
    3. GM-CSF (Leukine®) - no apparent benefit over G-CSF
    4. CSFs reduce infections, febrile neutropenia and short-term mortality (see below)
  3. Thrombocytopenia
    1. Thrombopoietin (TPO) - truncated version is used as "MGDF" and appears active
    2. PEG-recombinant human megakaryocyte growth and development factor (MGDF) [26,27]
    3. IL-11 - week activity, dose related side effects [10]
    4. IL-6 and IL-1a both cause marked dose related side effects, especially inflammation
    5. All of these agents are currently in clinical trials for thrombocytopenia
    6. TPO prior to autologous platelet donation increases harvested platelets 2-4 fold [42]
    7. TPO stimulated, cryopreserved autologous platelets very effective for alleviating chemotherapy induced thrombocytopenia [42]
  4. Erythropoietic Stimulating Agents (ESA) [3,28]
    1. Erythropoietin (EPO) recombinant (Epogen®, Procrit®, others) and darbepoetin Aranesp®)
    2. EPO is usually given three times weekly
    3. Darbepoetin (Aranesp®) is a long acting EPO given once weekly SC or IV
    4. Preferred over transfusion for chemotherapy induced or disease-associated anemia
    5. Recommended only with baseline serum EPO levels <200 mU/mL or hemoglobin <9gm/dL
    6. Improves quality of life when Hb increased to 11-12gm/dL (not higher)
    7. Used to maintain Hb 10-12gm/dL, which usually ameliorates symptoms
    8. Higher levels of Hb stimulated by ESAs associated with increased mortality [3]

D. Treatment of Severe Neutropenia [29,30,31] navigator

  1. Definitions
    1. Neutropenia <1500 neutrophils / µL (mm3)
    2. Moderate (Grade IV) Neutropenia <500 neutrophils / µL
    3. Severe Neutropenia <200 neutrophils / µL
    4. Moderate and severe neutropenia carry increased risks for severe bacterial infection
  2. CSFs in Chemotherapy Induced Neutropenia [8,9]
    1. Reduces infection risk 3.8% versus 3.1% on placebo [8]
    2. Reduces febrile neutropenia from 40-44% to 22-25%
    3. Reduces hospital days and at least short-term mortality (5.7% to 3.4% on drug) [9]
  3. G-CSF (filgrastim; Neupogen®) [31,32]
    1. Stimulates production of Granulocytes from committed precursor
    2. Acts on relatively mature cell types
    3. Side effects: fever
    4. ~5µg/kg daily subcutaneous (sc) dosing
    5. Reduces hospitalization and possibly mortality in febrile neutropenic patients
    6. Reduces duration of neutropenia in afebrile patients without clinical benefits [33]
    7. Appears to be safe in patients with myelocytic leukemias with neutropenia [34]
  4. Pegfilgrastim (Neulasta®)
    1. Pegylated version of G-CSF
    2. Single 6mg sc dose equivalent to 10-14 days of G-CSF
    3. Approved for management of chemotherapy related neutropenia in patients with non- myeloid malignancies who are receiving chemotherapy at >2 week intervals
  5. GM-CSF [31] (Leukine®)
    1. Stimulates production of Monocytes and granulocytes from multipotential precursor
    2. Reduces incidence of febrile periods and number of hospital days
    3. Side effects: bone pain, fever, rigors, malaise, nausea, vomiting
    4. No apparent clinical benefit over G-CSF
  6. Autologous Stem Cell Transplantation [35]
    1. Harvest of CD34+ stem (progenitor) cells prior to high dose chemo- or radiotherapy
    2. CD34+ cells are expanded ex vivo using growth factor combinations
    3. Reinfusion of cells after myeloablative therapy is well tolerated
    4. Cells reconsitute neutrophils (and other hematopoietic lineages) rapidly
    5. Neutropenia will occur for 0-2 days in most patients with this recovery modality
    6. Platelet counts generally >20K/µL with this recovery modality
  7. Prevention of Infections
    1. Prophylaxis with ciprofloxacin better than TMP/SFX (except for PCP coverage)
    2. Addition of Penicillin V po to quinolone reduces incidence of streptococcal infections
    3. Fluconazole may prevent candida infections but leads to resistant organisms
    4. Increased incidence of resistant organisms, especially for nosocomial pathogens
    5. PCP (Pneumocystis carinii pneumonia) more common in glucocorticoid treated patients
    6. CSFs reduce infections, febrile neutropenia, short-term mortality (see below) [8,9]
  8. Irinotecan Induced Neutropenia [49]
    1. Deficiency of UGT1A1 enzyme (usually due to UGT1A1*28 homozygosity) associated with increased diarrhea and myelosuppression
    2. Invader UGT1A1 Molecular Assay detects UGT1A1*28 allele; homozygous patients should receive reduced irinotecan doses [50]

E. Fever and Neutropenia [36] navigator

  1. Requires rapid institution of antimicrobial therapy
    1. High risk of death due mainly to gram negative infections
    2. Enterococci (from gut) and staphylococci (from skin) also problematic
  2. Other Infections
    1. Suspected cellulitis: add vancomycin 1gm every 12 hours (renal dosing required)
    2. Suspected abdominal source: add metronidazole 500mg q8 hrs
    3. Parenteral nutrition: high suspicion for yeasts (especially Candida ssp)
    4. Pneumocystis carinii pneumonia (PCP)
  3. Intravenous antibiotics must be started for any fever with ANC<500/µL
  4. Cultures most frequently negative
    1. Many patients with fever and neutropenia have fever of unknown origin, FUO
    2. Two or three sets of blood cultures must be obtained
    3. Urine Culture
    4. Sputum Culture
    5. Consider throat culture
    6. Wound culture
    7. Cell-wall-deficient bacteria (mainly staphylococcus or baccilus) cause a substantial portion of "culture-negative" febrile episodes in BMT patients [37]
  5. Blood Cultures
    1. Two sets of blood cultures should be drawn on all patients with suspected infection
    2. Cancer patients with central venous catheters often have centrally drawn blood samples
    3. Negative results on cultures from central and peripheral venous lines are useful [38]
    4. Positive predictive value of centrally drawn cultures was only 63% (false positives) [51]
    5. Therefore, positive cultures from central venous lines should be interpreted cautiously
  6. Common Organisms
    1. Gram negative rods, especially Pseudomonas species, E. coli
    2. Gram positive cocci, especially with indwelling catheters (mainly staphylococci)
    3. Anaerobes including Clostridial ssp.
  7. Symptoms and signs of infection may be highly blunted
    1. Fever ± pain may be only symptom
    2. Erythema seldom occurs (no neutrophilic infiltrate)
    3. Purulence and/or swelling very unusual
    4. Rarely find infiltrates on radiograph until ANC returns
    5. Physical exam should include perirectal assessment but NO digital rectal examination
    6. Abdominal pain should prompt evaluation for neutropenic enterocolitis [39]
  8. In HBsAg+ patients receiving cancer chemotherapy, LAM prophylaxis prevents HBV reactivation by >80% and may eliminate HBV-related hepatic failure [52]

F. Mucositis / Stomatitis navigator

  1. Common Agents
    1. 5-fluorouracil, capecitabine
    2. High dose cyclophosphamide, chemoradiotherapy
    3. High dose doxorubicin or methotrexate can also cause severe mucositis
    4. Most common with ablative chemotherapy used in stem cell rescue protocols
  2. Irinotecan causes a secretory-like diarrhea without epithelial destruction
  3. When oral mucositis occurs, it is nearly always associated with GI mucositis
  4. Complications
    1. Severe Pain
    2. Dehydration
    3. Infection - fungal, enteral, oral
    4. Mucosal damage in neutropenic patients can lead to typhlitis (see above)
    5. Malnutrition
  5. Treatment Overview
    1. Adequate hydration ± parenteral nutrition is essential
    2. Pain medications for severe mucositis: intravenous opiates often required
    3. Topical Anesthetics: benzocaine, viscous lidocaine, others
    4. Combinations: Kaopectate, diphenhydramine (Benadryl®), Lidocaine (KBL)
    5. Chlorhexidine rinse (Peridex®), Orabase®
    6. Nystatin / Clotrimazole: rinse to prevent candidal infections
    7. Pilocarpine (cholinergic agonist stimulates salivary glands) 20mg per day po
    8. For lower GI mucositis with diarrhea, Kaopectate + generous fluids
    9. Amifostine (Ethyol®) approved for xerostomia reduction in head and neck cancers
    10. Amifostine appears to absorb free radicals and also protects against renal damage
    11. Palifermin (Kepivance®)
  6. Palifermin (Kepivance®) [48]
    1. Recombinant N-terminus truncated version of Keratinocyte Growth Factor (KGF)
    2. Heparin binding member of fibroblast growth factor family (fomerly FGF-7)
    3. Dose is 60µg/kg per day x 3 days intravenously before initiation of conditioning regimen
    4. Reduced Grade 3/4 mucositis, pain medications, parenteral nutrition
    5. Approved for use prior to stem cell transplantation for hematologic malignancies
    6. Concern for use with solid malignancies due to expression of KGF receptors

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