Toxicities of Chemotherapy

1
Toxicities of Chemotherapy

• Drug toxicity is often a diagnosis of exclusion.
• Dose, schedule, and combination make a
  difference.
• Not all toxicities are known.
• Treatment is supportive.

2
Classification of cytotoxic agents
Alkylating Agents
Anti- Metabolites
Mitotic Inhibitors
Antibiotics
Others

• Busulfan Cytosine Etoposide Bleomycin L-sparaginas
  e
• Carmustine Arabinoside Teniposide Dactinomycin Hyd
  roxyurea
• Chlorambucil Floxuridine Vinblastine Daunorubicin
  Procarbazine
• Cisplatin Oxaliplatin Fluorouracil Vincristine Dox
  orubicin Camptotecan
• Cyclophosphamide Mercaptopurine Vindesine Mitomyci
  n-c Topotecan
• Ifosfamide Methotrexate Taxoids Mitoxantrone
• Melphalan Plicamycin

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Action sites of cytotoxic agents
S (2-6h)
G2 (2-32h)
Vinca alkaloids
M (0.5-2h)
Mitotic inhibitors
Taxoids
Alkylating agents
G1 (2-?h)
Cell cycle level
G0
4
Action sites of cytotoxic agents
PURINE SYNTHESIS
PYRIMIDINE SYNTHESIS

• 6-MERCAPTOPURINE
• 6-THIOGUANINE
• METHOTREXATE
• 5-FLUOROURACIL
• HYDROXYUREA
• CYTARABINE

RIBONUCLEOTIDES
DEOXYRIBONUCLEOTIDES
ALKYLATING AGENTS ANTIBIOTICS
DNA
CPT-11, topotecan
ETOPOSIDE
Topoisomerase I, II
RNA
L-ASPARAGINASE VINCA ALKALOIDS TAXOIDS
PROTEINS
MICROTUBULES
ENZYMES
5
Side effects of chemotherapy
Alopecia Pulmonary fibrosis Cardiotoxicity Lo
cal reaction Renal failure Myelosuppression Phl
ebitis

• Mucositis
• Nausea/vomiting
• Diarrhea
• Cystitis
• Sterility
• Myalgia
• Neuropathy

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Myelosuppression (1)
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Myelosuppression (2)

• Granulocytes then platelet then RBC.
• Variation in which cell lines are most
  suppressed.
• Pelvic or spinal radiation or multiple courses of
  C/T will suffer more severe and prolonged
  myelosuppression
• Other causes of cytopenia cancer infiltration in
  the marrow, other drug toxicity, sepsis.

8
Management of Myelosuppression 1

• Severe neutropenia (WBClt1000 or PMNlt500) with
  fever
• Sepsis work up
• Strong antibiotics
• G-CSF Filgrastim or Granocyte 5-10mg/Kg sc QD
• Reverse isolation
• Follow up WBC q2-3d

9
Management of Myelosuppression 2

• Moderate neutropenia WBC 1000-3000 or PMN
  500-1500
• With infection signs treat as neutropenic fever
• Without infectious signs close follow-up, avoid
  infection
• Modify C/T doses in the following courses

10
Management of Myelosuppression 3

• P-RBC transfusion when Hblt8 or with CV adverse
  effects
• Platelet transfusion when plateletlt20,000 or with
  severe bleeding signs

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Drugs which cause mucositis
12
Mucositis (1)

• Whole GI tract, from mouth to rectum, is
  susceptible.
• Mild mouth sores to severe bloody diarrhea.
• Breakdown of the mucosal barrier ? portal for the
  entry of infectious agents.
• High dose C/T with or without R/T frequent cause
  severe mucositis.
• Candida and herpes viruses cause or worsen
  stomatitis C. difficile ? pseudomembranous
  colitis

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Mucositis (2) treatment

• Keep mouse clean with soft swabs, saline, or
  chlorhexidene gluconate (scodyl).
• Topical anesthetics salcoat, dexaltin
• Systemic narcotics
• Parenteral nutrition

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Pulmonary toxicity (1)

• Pneumonitis/fibrosis, acute pleuritic pain,
  hypersensitivity, pulmonary edema.
• Dyspnea, dry cough, fatigue, fever.
• Acute presentation appears gradually over
  several weeks. DD with infection, radiation,
  cardiogenic edema, pulmonary embolus, hemorrhage,
  leukoagglutinin reaction, and progressive tumor.

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Pulmonary toxicity (2)

• Pathology endothelial cell swelling, necrosis of
  type I pneumocytes, atypical proliferation of
  type II cells, generalized fibrosis in end-stage.
• CXR normal diffuse reticulonodular pattern, or
  mass-like lesion (bleomycin), pleural effusion or
  hilar LAP (MTX).
• Biopsy ? Controversial.
• Treatment supportive. Steroid ?

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Pulmonary toxicity (3)

• Bleomycin risk factors gt450500 mg, age gt 70,
  prior or concomitant R/T, CTX, Bolus rather
  than infusion.
• O2 may be harmful, use it only when necessary.

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Cardiovascular toxicity (1)

• Rare Sporadic (most cardiac events in cancer
  patients are related to preexisting cardiac
  disease or tumor involvement)
• Anthracyclines (doxorubicin, daunorubicin,
  epirubicin, idarubicin)
• ECG changes (40 doxorubicine users) ST-T, APC,
  VPC, ST (transient), decrease QRS voltage (may be
  permanent)
• Only very rarely sudden death, no needs to
  discontinue drug.

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Cardiovascular toxicity (2) Myocardial ischemia
and Infarction

• Very rarely.
• R/T accelerated atherosclerosis, symptomatic
  years later.
• Vinca alkaloid bleomycin some incidences of
  AMI.
• 5-FU, 4 anginal symptoms.
• Nitrates and calcium channel blockers helpful.

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Cardiovascular toxicity (3) Cardiomyopathy and
Pericarditis

• Anthracyclines and high dose CTX may produce
  fatal cardiomyopathy.
• Acute drop in EF (hrs wks), pericardial
  effusion, CHF.
• Chronic cardiomyopathy (doxorubicin 550 mg/m2 1
  10)
• Symptoms nonspecific, tachycardia, dyspnea,
  cardiomegaly, peripheral and pulmonary edema.
• EM myofibrillar loss and sarcoplasmic dilatation
  with coalescence into cytoplasmic vaculoes

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Cardiovascular toxicity (4) Cardiomyopathy and
Pericarditis

• Occurs in 30 days 1 year after treatment.
• Reversible and irreversible CHF, may be fatal.
• No specific therapy (ICRF-187 ?), only
  supportive.
• Further use of doxorubicn is contraindicated.

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Cardiovascular toxicity (5) CTX

• 1.55 g/m2 severe hemorrhagic myopericarditis.
• Onset within 48 hr.
• Patients rapidly die of cardiogenic shock.
• Edema, tachycardia and tachycardia, 7 10 days
  after therapy. May have decreases in QRS voltage.
  
• Treatment is supportive. Survive the acute phase
  may have complete recovery.

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Neurotoxicity (1)

• Rarely severe enough to be admitted to ICU.
• Consider other causes tumor, steroids,
  metoclopramide, benzodiazepine.
• Acute Cerebellar Syndrome

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Neurotoxicity (2) Acute Encephalopathy
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Neurotoxicity (3)

• Acute Paraplegia
• IT cytarabine, MTX, Thio-TEPA acute reversible
  arachnoiditis, paralysis exceedingly rarely, may
  or may not be reversible.
• Other Neuropathies
• Cisplatin dose-dependent, ototoxicty distal
  sensory neuropathyataxia.
• Etoposide anecdotal, mild distal paresthesias
  DTR depression.
• Vinca alkaloids, symmetrical areflexia, distal
  paresthesias symmetrical motor weakness, jaw
  pain, cranial nerve palsies, paralytic ileus.
• Procarbazine 1020, decreased DTR, mild distal
  paresthesias usually reversible.

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Neurotoxicity (4)Vinca Alkaloids

• SIADH
• Peripheral neuropathy symmetric mixed
  sensorimotor neuropathy quadriparesis dose
  related and gradual onset No treatment.
  Transient muscle pain.
• Cranial nerve palsies vocal cord paralysis,
  dysphagia, optic atrophy, ptosis,
  ophthalmoplegias or fascial nerve paralysis
  abrupt onset, bilateral, usually reversible.
• Autonomic neuropathy ileus, bladder atony,
  impotence, and orthostatic hypotension usually
  reversible, may need NG tube drainage.

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Neurotoxicity (5) L-asparaginase

• Incidence 2550
• Mild depression, drowsiness to confusion, stupor,
  and coma.
• Rapid onset, clears rapidly after the end of
  therapy.
• Cause unknown, some cases due to clotting
  abnormalities.

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Neurotoxicity (6)Cytosine arabinoside

• Seen in high dose (23 g/m2 bid).
• High risk groups gt 55 y/o, larger cumulative
  dose.
• Cerebellar changes are more severe than cerebral
  ones.
• Onset 57 days
• Signs intention tremor, dysarthria, horizontal
  nystagmus limb and truncal ataxia (even unable
  to walk or eat) somnolence, disorientation,
  memory loss, seizure and coma.
• May abate over days weeks, may be irreversible,
  even fatal.

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Neurotoxicity (7) Methotrexate

• Seen in high dose (17 g/m2 ).
• Incidence 215.
• Onset hours weeks.
• Signs develop abruptly, resemble a stroke
  (hemiplegia, speech disorder), focal or
  generalized serzures. Recover over several days.
• Supportive care.
• Intrathecal MTX can cause acute arachnoiditis,
  cranial nerve palsies, paralysis, or seizures.
  Recovery is often but not always.
• Necrotizing leukoencephalopathy begins
  insidiously months after treatment.

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Renal and Urinary ToxicityCisplatin

• Focal necrosis of the distal tubules and
  collecting ducts.
• Creatinine rises a few days after therapy, peaks
  at 314 days
• Renal magnesium wasting, hypocalcemia,
  hypokalemia,
• Management iv or im Mg, and other supportive.

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Renal and Urinary ToxicityMTX

• Usually reversible over 23 weeks.
• Impaired renal excretion cause profound cytopenia
  and mucositis.
• Patients with third space fluid reservoir
  (pleural effusion or ascites) may have prolonged
  toxicities due to slow release MTX into
  circulation.

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Renal and Urinary Toxicity CTX (1)

• Bladder fibrosis, bladder cancer, hemorrhagic
  cystitis
• Hemorrhagic cystitis idiosyncrasy, high
  incidence in prolonged or high dose therapy also
  high in ifosfamide.
• Prevention mesna (sulfhydryl group neutralize
  acrolein) adequate prehydration (NS furosemide
  ) with frequent voiding notice SIADH.
• Clinical presentation
• Onset within few days.
• Hematuria, dysuria, urinary urgency the bleeding
  usually stops after 1 month.

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Renal and Urinary ToxicityCTX (2)

• Treatment
• Stop CTX.
• Vigorous hydration.
• Adequate platelet.
• Constant bladder irrigation.
• Instillation of Alum, prostaglandin analogue,
  formalin (severe pain).
• Urinary diversion.

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Other toxicities

• Nausea vomiting
• Primperan
• Serotonin antagonists dexamethasone
• Vesicants (doxorubicin, mitomycin C,
  vincristine)????
• CPT-11 20 severe diarrhea, some may be fatal,
  ????imodium, ofloxacin, adequate hydration

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Interferon- a (1)

• Indication CML, renal cell carcinoma, hairy cell
  leukemia, low-grade lymphoma.
• Flu like symptoms malaise, myalgias, headaches,
  tachycardia, chills, and fever.
• Begins within 6 hours and lasts 48 hours.
• The intensity will decrease or even disappear
  after 12 weeks.
• Chronic fatigue syndrome may occur after
  prolonged therapy.
• Cardiac toxicity (idiosyncrasy) acute
  arrhythmias, myocardial infarction, and sudden
  death, and congestive cardiomyopathy.
• High dose (gt 100MU) acute reversible
  neurological toxicity lethargy, confusion, and
  seizures.