Chemotherapeutic Agents

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Chemotherapeutic Agents
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Introduction

• Classification of Drugs
• Cell-cycle specificity
• Mechanism of Action
• Indication
• Side effects

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Antimetabolites

• Cell-cycle specific
• Act in S-phase
• Inhibit enzyme production for DNA synthesis
• Lead to strand breaks or incomplete DNA strands

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Cytosine Arabinoside

• Also called Ara-C or Cytarabine
• Treatment for Leukemias and Lymphomas
• Variety of dose schedules/routes
• Myelosuppression, alopecia (dose dependant), NV,
  mucositis, diarrhea, conjunctivitis, acral
  redness, liver and kidney dysfunction, neurologic
  dysfunction (high dose)
• Non-vesicant

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5-Flurouracil (5-FU)

• Treatment for GI, breast, and ovarian cancers
• Variety of dose schedules
• Mucositis and Diarrhea, mild alopecia,
  photosensitivity, darkening and sclerosing of
  veins, skin changes, mild to no NV
• Potentiates radiation therapy--may be given
  concurrently
• Leucovorin increases toxicity
• Non-vesicant

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Methotrexate

• Treatment for lymphomas, leukemias, ovarian,
  breast, lung, testicular, cervical, and CNS mets
• May be given for non-cancer dx
• Variety of dose schedules/routes
• Mucositis and diarrhea, NV, alopecia,
  Myelosuppression, photosensitivity, renal
  toxicity
• Given with Leucovorin (rescue)
• Non-vesicant

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Fludarabine

• Treatment for CLL
• 25 mg/m2 IV for 5 days
• Given as 30 minute infusion
• Myelosuppression, nausea, slight alopecia, rash,
  diarrhea

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Capecitabine (Xeloda)

• Treatment for breast cancer
• Pro-drug -- turns to 5-FU in body
• 2,500 mg/m2 orally for 14 days on and 7 days off
• Take with food
• Diarrhea, Mucositis, numbness, tingling, itching
  of hands and feet (hand and foot syndrome)

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Gemcitabine (Gemzar)

• Treatment for pancreatic, lung, and many other
  cancers
• 1000mg/m2 IV every week up to 7 weeks in a row
• Given as a 30 minute infusion--longer infusions
  increase toxicity
• Myelosuppression, NV, fatigue, increased liver
  enyzmes, alopecia
• Non-vesicant

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Vinca Alkaloids

• Cell-cycle Specific
• Act in late G2 phase, M phase, and S phase
• Block DNA and RNA production, prevent cell
  division, inhibit microtubule formation

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Vinorelbine (Navelbine)

• Treatment for lung, breast cancer
• 30 mg/m2 IV weekly
• VESICANT
• Given IV push over 6 -10 min through side port of
  fast running IV (furthest from IV site), f/b 100
  cc flush
• Myelosuppression, Peripheral neuropathy, NV,
  mild alopecia

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Vincristine (Oncovin)

• Treatment for leukemias, breast, lymphoma, SCLC,
  sarcoma
• 1.4mg/m2 IV weekly
• DOSE NOT TO EXCEED 2 mg
• VESICANT
• Peripheral neuropathy, constipation, paralytic
  ileus, jaw pain
• Neuropathy is cumulative
• FATAL IF GIVEN INTRATHECALLY

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Vinblastine (Velban)

• Testicular, Head and neck cancer, Hodgkins
  disease, Kaposis sarcoma
• 4 - 18 mg/m2 IV weekly
• VESICANT
• Peripheral neuropathy, constipation,
  myelosuppression, mild alopecia, jaw pain
• Less neuropathy than vincristine

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Epipodophyllotoxins

• Cell-cycle specific
• Work in late G2 and S phase
• Interfere with topoisomerase II enzyme
• Stops cell replication in pre-mitotic phase

15
Etoposide (VP-16)

• Breast, testicular, SCLC, lymphomas
• 100 mg/m2/day x 3 days q 28 days
• Non-vesicant
• Myelosuppression, NV, alopecia, orthostatic
  hypotension
• Rapid infusion causes hypotension-given over
  45-60 min
• Must be dilute or will precipitate

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Taxanes

• Cell-cycle specific
• Active in G2 and M phase
• Stabilize the microtubule structure
• Cells cannot divide

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Paclitaxel (Taxol)

• Breast, ovarian, SCLC
• Given IV over 24hrs, 3 hrs, or 1 hr
• Myelosuppression, alopecia (severe), peripheral
  neuropathy, hypersensitivity rxns, myalgias,
  severe fatigue
• Pre-meds Dexamethasone 20 mg po 12 6 hrs
  prior, Pepcid or Tagamet, Benedryl plus
  anti-emetic
• Need NON-PVC tubing with 0.2 micron in-line
  filter -- NON-PVC bag or bottle
• IRRITANT
• When given with other chemo drugs give Taxol
  first

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Docetaxel (Taxotere)

• Breast, NSCLC, head and neck, ovarian
• 60 to 100 mg/m2 IV every 3 weeks
• Myelosuppression, myalgias, hypersensitivity,
  peripheral neuropathy, alopecia (severe)
• Pre-med Dexamethasone 8 mg po bid starting 1 day
  prior and continuing 4 days after
• Non-PVC tubing and bottle (no filter)

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Camptothecins

• Cell-cycle specific
• Act in S phase
• Inhibit topoisomerase I
• Causes double-strand DNA changes

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Topotecan (Hycamtin)

• Ovarian, salvage therapy
• 1.5 mg/m2 IV daily x 5 days q 3 weeks
• Myelosuppression, diarrhea, mild alopecia

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Irinotecan (Camptosar)

• Metastatic colon and rectum
• 125 mg/m2 IV weekly x 4 weeks
• Diarrhea (severe), Myelosuppression, alopecia
• Diarrhea MUST be treated -- patients need to go
  home with antidiarrheal and know how to use it

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Miscellaneous

• Cell-cycle specific
• Work in a variety of ways
• Inhibit Protein synthesis
• Act in S phase
• Inhibit RNA and DNA synthesis

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L-Asparginase (Elspar)

• Leukemia
• 1,000 - 6,000 IU/m2 IM
• Hypersensitivity, anaphylaxis, hepatoxicity, NV
  (slight), fever
• ALWAYS give test dose prior to initial dose-test
  dose given intradermally
• Also give test dose if pt has not had in more
  than 1 week
• IM administration decreases hypersensitivity
  reactions

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Pegaspargase (Oncaspar)

• Leukemics who are sensitive to Elspar
• 2,500 IU/m2 IM every 14 days
• Hepatotoxicity, coagulopathy, may have some
  hypersensitivity rxns
• Less hypersensitivity than Elspar - may not need
  test dose
• VERY expensive

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Hydroxyurea (Hydrea)

• Leukemias, Malignant melanoma, head and neck
  cancer, ovarian
• 20 - 30 mg/kg PO q day
• Myelosuppression, NV (mild), mucositis,
  constipation or diarrhea
• Dose is adjusted based on blood counts

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Alkylating Agents

• Cell-cycle Nonspecific
• Break DNA helix strand
• Interfere with DNA replication

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Cisplatin

• GU cancers, lung, head and neck, sarcomas,
  testicular, renal cell, esophageal
• Doses no higher than 100 mg/m2
• Monitor K, Mg, Creatinine
• Severe and prolonged NV, nephrotoxocity,
  ototoxicity, myelosuppression, alopecia (mild)
• Rigorous hydration needed to prevent renal
  toxicity
• Irritant

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Carboplatin

• Ovarian, testicular, head and neck, lung,
  cervical
• Varied dosing sometimes ordered as AUC (area
  under the curve)
• Thrombocytopenia, NV, hyper-
  sensitivity, myelosuppression, renal/hepatic
  toxicity
• No need for rigorous pre- or post-hydration

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Oxaliplatin

• Second line therapy for metatstatic colorectal
  cancer
• Neuropathy starting within hours exacerbated by
  exposure to cold
• Acute and chronic neuropathy
• Neutropenia (? w/ 5-FU), Anemia Thrombocytopenia
• Renally excreted
• Irritant use central line

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Cyclophosphamide (Cytoxan)

• Breast, lung, prostate, ovary, leukemias,
  lymphomas, Multiple Myeloma, head and neck
• Varied dosing schedule/route
• Hemorrhagic cystitis, myelosuppression, NV,
  alopecia, SIADH, nasal burning
• Patient should drink 8 -10 glasses of water per
  day

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Ifosfamide (Ifex)

• Lung, testicular, lymphomas, sarcomas
• 1.2 gm/m2 IV days 1-5 q 3-4 wks
• ALWAYS given with Mesna
• Hermorrhagic cystitis, NV, alopecia,
  myelosuppression, neurotoxicity
• Mesna dose should be 20 of the Ifosfamide dose

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Mechlorethamine HCl(Nitrogen Mustard)

• Leukemias, lymphomas
• 6 mg/m2 IV on day 1 and day 8 q 4 weeks
• Myelosuppression, NV, chills, fever, pain at IV
  site
• VESICANT
• Flush with 125 - 150 cc NS
• Stable for only 10 to 15 minutes use immediately
  after mixing

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Dacarbazine (DTIC)

• Lymphomas, Sarcoma, Melanoma
• 75 - 1500 mg/m2
• Myelosuppression, NV, alopecia, flu-like
  syndrome, renal and liver toxicity, diarrhea
• VESICANT

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Thiotepa

• Bladder, breast, ovarian, lymphomas
• 0.3-0.4 mg/kg IV at 1 - 4 wk intervals 0.6-0.8
  mg/kg for bladder (intracavitary) administration
• Myelosuppression, rash, fever, NV
• Monitor renal function if given IV

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Anti-tumor Antibiotics

• Cell-cycle Nonspecific
• Bind with DNA
• Inhibit DNA and RNA synthesis

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Doxorubicin (Adriamycin)

• Breast, ovary, prostate, stomach, lung, liver,
  head and neck, multiple myeloma, lymphomas,
  leukemias
• 40-75 mg/m2 q 3 weeks
• Myelosuppression, NV, alopecia, mucositis,
  cardiotoxicity, radiation recall,
  photosensitivity, red urine
• VESICANT
• May cause flare reaction
• MUGA / Echocardiogram before dosing
• Lifetime cumulative dose 450-550mg/m2

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Liposomal Doxorubicin (Doxil)

• Refractory ovarian, Kaposis sarcoma
• 50 mg/m2 IV q 4 weeks
• Myelosuppression, palmar-plantar
  erythrodysesthesia, cardiotoxicity, mucositis,
  NV, rash, alopecia
• Start infusion at 1 mg/min and check for
  flushing, SOB, facial swelling, hypotension. If
  none, give over 30-60 minutes
• Irritant not vesicant

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Bleomycin (Blenoxane)

• Lung, head and neck, cervical, GYN cancers, GU
  cancers, lymphomas
• 10-20 units/m2 IV, IM, or SQ 1-2 times per week
• Hypersensitivity, anaphylaxis, alopecia,
  photosensitivity, renal/hepatotoxicity, fever,
  chills, pulmonary fibrosis
• Test dose of 1-2 units before 1st dose
• Cumulative lifetime dose 400 units due to risk
  for pulmonary fibrosis

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Mitomycin - C

• GI tumors, breast, lung, head and neck,
  esophageal, bladder, multiple myeloma
• 20 mg/m2 IV q 6-8 weeks
• Myelosuppression, alopecia, mucositis, renal /
  pulmonary toxicity, fatigue
• VESICANT
• Nadir is 4 to 8 weeks
• Brochospasm can occur when given simultaneously
  or after Vinca alkaloid
• Extravasation can occur distant from IV site

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Mitoxantrone (Novantrone)

• Breast, lymphomas, leukemia (ALL)
• 12 - 14 mg/m2 every 21 days
• Myelosuppression, alopecia, cardiotoxicity
• Urine blue-green with 1st post void
• VESICANT

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Hormonal Therapy

• Cell-cycle Nonspecific
• Interfere with hormone receptors
• Interfere with protein synthesis in all phases of
  cell cycle

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Glucocorticoids

• Prednisone, dexamethasone, etc.
• Breast, lymphomas, multiple myeloma, leukemias,
  CNS tumors or mets
• Various dosing schedules
• Fluid retention, hyperglycemia, GI irritation,
  masks infections, mood swings, moon face,
  osteoporosis, perineal burning with rapid infusion

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Tamoxifen

• ER, postmenopausal breast cancer
• 10 mg tab po BID
• Vaginal bleeding/discharge, hot flashes, NV,
  risk of uterine cancer
• Usually given for 5 years-no evidence for
  continued use
• Given as preventative in high-risk women

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Progestins

• Depo-Provera Megace
• Breast, renal cell
• Depo-Provera 400-1,000 mg IM q wk Megace 40 -
  320 mg/day in divided doses PO
• Fluid retention, headache, vaginal
  bleeding/spotting, increased appetite,
  thrombophlebitis
• Megace used as appetite stimulant
• Depo-provera used to prevent menses in
  thrombocytopenic patients

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Leuprolide (Lupron)

• Prostate, breast cancer
• Dose varies with protocol
• Gynecomastia, hot flashes, NV, headache, bone
  pain
• Symptoms may worsen in first few weeks of therapy.

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Goserelin acetate (Zoladex)

• Prostate, breast cancer
• Dose varies with protocol
• Hot flashes, gynecomastia, NV
• Given as depot injection SQ into abdomen (with
  14-16 gauge needle) once a month or every 3 months

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Nitrosoureas

• Cell-cycle Nonspecific
• Break DNA helix
• Interfere with DNA replication
• Cross blood-brain barrier

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Carmustine (BCNU)

• Lymphomas, CNS tumors, multiple myeloma,
  melanoma, BMT
• 75-100 mg/m2 IV x 2 days or 200 mg/m2 IV single
  dose q 6-8 wks
• NV, myelosuppression, renal/liver toxicity,
  pulmonary fibrosis
• Nadir 4-6 weeks
• Crosses blood/brain barrier
• Rapid infusion causes facial flushing and
  hypotension

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Monoclonal Antibodies

• Cell-cycle Nonspecific
• Uses antibody to target specific cells
• Bind to markers on cell surface
• Induce cell death (apoptosis)
• Initiate complement system which results in cell
  phagocytosis

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Antibodies/Antigens
Antibodies
Antigens
CELL
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How Antibodies Work
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How MoAbs Are Produced
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Various Types of MoAbs
Adapted from LoBuglio A, et al. Crit Rev Oncol
Hematol. 199213273.
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Monoclonal Antibodies (MoAbs)

• momab- murine antibody
• ximab- chimeric antibody
• xumab- humanized antibody

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Rituximab (Rituxan)

• Leukemias, lymphomas, ITP, Waldenstroms
  macroglobulinemia
• 375mg/m2 IV schedule varies
• Start at 50 mg/hr increase gradually if no
  reaction.
• Infusion-related side effects fever with rigors,
  hypotension, allergic reactions, NV, pain
• Pre-med Tylenol and Benedryl

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Ibritumomab (Zevalin)

• Anti-CD 20 antibody bound to Tiuxetanwhich binds
  to Yittrium 90 or Indium 111
• Dose 0.4 mCi/kg
• Given in Nuclear Medicine
• Cannot be given if platelets lt 100,000
• Dose reductions based on platelet count

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Trastuzumab (Herceptin)

• Breast, prostate
• Dose varies with protocol
• Cardiotoxicity, myelosuppression, allergic
  reactions, infusion reactions (chills, fever,
  headache) common with 1st infusion- give over 30
  min
• When given with other chemo- therapeutic
  agents-give first
• MUGA or Echocardiogram before 1st dose
• Pre-med with Tylenol and Benedryl

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Gemtuzumab (Mylotarg)

• AML (leukemia)
• Antibody calicheamicin (antitumor antibiotic)
• Mylosuppression, longstanding thrombocytopenia,
  fatigue, myalgias, anorexia, chills and fever
• Given over 2 hours x 2 doses 7 days apart
• Pre-med with Tylenol and Benedryl

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Alemtuzumab (Campath)

• Chronic Lymphocytic Leukemia
• Failed first line therapy with Fludarabine
• T-cell Leukemia, Mycosis Fungoides, NHL
• Binds to CD-52 ? cell lysis
• Severe Myelosuppression
• Start at 3 mg daily over 2 hours
• When no reactions, increase to 10 mg
• When tolerated increase to 30 mg M-W-F for 12
  weeks.
• Severe infusion related reactions
• Premedicate with Tylenol, Benedryl, and
  Hydrocortisone

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Biologic Response Modifiers

• Cell-cycle Nonspecific
• Stimulate immune system-primarily lymphocytes
• Cause release of cytokines
• Not effective as single agents

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Interferons

• Leukemias, lymphomas, multiple myeloma, melanoma,
  hepatitis, renal cell, Kaposis sarcoma
• Dose varies depending on formulation and disease
• Flu-like syndrome, fever, malaise, anorexia,
  diarrhea, rash
• Usually self-administered best taken at HS
• Pre-med with Tylenol

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Aldesleukin (IL-2)

• Renal cell, malignant melanoma
• Dose varies depending on protocol
• Toxicity is dose related
• Capillary-leak syndrome, hypotension, cardiac
  arrhythmias, pulmonary edema, mental status
  changes, rash with pruritis, diarrhea,
  lymphocytosis, weight gain,edema
• Pre-medicate as ordered

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Immunoglobulin (IgG)

• ITP, TTP, anemias, leukemias, post BMT
• Dose varies with manufacturer
• Chills, fever, hypotension, dyspnea, anaphylaxis,
  urticaria, edema of lips and tongue
• Monitor vs q 15 min x 4 then q hr
• Start at slow rate and increase q 15-30 min until
  MAX rate (dependes on manufacturer)

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Chemoprotectants

• Not chemotherapy
• Given with chemotherapy protocol to decrease
  toxicities
• Side effects vary with drug
• Protect healthy cells but not cancer cells

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Mesna (Mesnex)

• Prophylaxis of acrolein-induced hemorrhagic
  cystitis
• IV bolus injection equal to 20 Ifex dose
  15-30min prior to Ifex and 4 and 8 hours after
  Ifex
• May be given concurrently as CI
• Run for 12 hours after Ifex done
• Oral dose
• Diarrhea, headache, nausea, fatigue (all mild)

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Amifostine (Ethyol)

• Reduction of renal toxicity from Cisplatin
  administration
• Protects salivary glands from RT
• Hypotension and nausea, lowers Ca
• Run NS at 500 cc/hr x 2 hrs
• Ondansetron 32 mg IV Dexamethasone 20 mg IV and
  Ativan 1 mg IV 1 hour prior to drug
• Give over 10 minutes approx 30 min. prior to
  Cisplatin-pt should be supine
• Stop infusion if systolic BP drops significantly
  from baseline

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Dexrazoxane (Zinecard)

• Reduces incidence and severity of cardiomyopathy
  from Adriamycin
• 101 Zinecard to Adriamycin
• Slow IV push or fast IV infusion 30 min prior to
  Adriamycin
• Not recommended with initiation of treatment
  used after Adriamycin cumulative dose gt 300mg/m2
• May lower response rate

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Leucovorin

• Given with Methotrexate to reduce toxicity to
  healthy cells
• A form of folic acid
• Taken up preferentially by healthy cells instead
  of Methotrexate which is taken up more by cancer
• For HD Methotrexate, given until methotrexate
  level in safe range
• Increases toxicity of 5-FU

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5HT3 receptor antagonists

• Ondansetron (Zofran) 32 mg IV or 4 to 8 mg po TID
• Granisetron (Kytril) 10 mcg/kg IV or 2 mg PO
  daily
• Dolasetron (Anzemet) 1.8 mg/kg IV or 100 mg po
• Work prophylactically in chemo Rx
• Less useful for delayed NV

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Emend

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