Complications of

Cancer Treatment
A 40 year old premenopausic female
was referred for adjuvant
chemotherapy of Stage II B (T2
N1Mo) Estrogen Receptor negative
her-2-neu 2+ (FISH) Invasive
Ductal Carcinoma of the left
breast. She had a left sided
Modified Radical Mastectomy three
weeks ago.
Case
 What information should be disclosed
during the oncologic consultation?
 What are the adverse reactions to
cancer treatment?
Case
The physician recommended the
following regimen for adjuvant
chemotherapy:
4 cycles of Doxorubicin +
Cyclophosphamide
followed by
4 cycles of Paclitaxel
with Trastuzumab for one year
and radiation to the chest wall and
Case
 What are the most likely acute adverse
reactions this patient will have during
chemotherapy?
 What is the known acute and long term
adverse reactions to doxorubicin?
 What other reactions are observed with
other agents?
 What are the long term adverse
reactions to chemotherapy
 What are the adverse reactions to
radiation?
Acute Reactions(1)
 Hair loss
 Nausea and vomiting
 Fatigue
 Mucositis
 Change in skin pigmentation
Acute Reactions (2)
 Myelosuppression
 Hypersensitivity
 Hepatotoxicity
 Neurotoxicity
 Vascular toxicity
Disclosure for Patients with Cancer
 Diagnosis
 Stage of disease
 Options for treatment
 Complications of treatment
 Acute
 Long term
 Prognosis
Adverse Reactions to Cancer
Treatment
Non-hematologic toxicities
•Nausea & vomiting
•Oral
•Gastrointestinal
•Pulmonary
•Cardiac
•Hair loss
•Gonadal dysfunction
•Second cancers
•Miscellaneous
Adverse reactions
Hematologic toxicities
•Anemia
•Leukopenia
Neutropenia
•Thrombocytopenia

Back
 Hair loss
 immense burden psychologically
and physically
 occurs within 2 to 3 weeks of
chemotherapy treatment
 normally resolves within 2 to 3
months after completion or
cessation of chemotherapy
Adverse reactions
 Therapeutic Interventions in Alopecia
 Decrease local delivery
 Scalp tourniquet
 Scalp hypothermia
 Protection of the hair bulb
 Topical minoxidil
 AS101
 Inhibitors of cyclin-dependent kinase
 Thiol solution
 Inactivate chemotherapy locally
 ImuVert
 Epidermal growth factor and fibroblast growth factor
 Topical cyclosporine
 Interleukin-1
 Topical calcitriol
 Liposome-entrapped monoclonal antibody
 Pulsed electrostatic field
Back
 Emetic syndromes related to
chemotherapy
 Acute
 occurring within the first 24 hours after
administration of CT (usually within 1 to 2 hours)
 generally most severe during the initial 4 to 6 hours.
 Delayed
 occurring 24 or more hours after CT
 range of 16 to 24 hours

maximal risk at 48 hours
 most commonly associated with cisplatin,
carboplatin, cyclophosphamide, and doxorubicin
 Anticipatory
 learned or conditioned response that typically occurs
before, during, or after the administration of CT

Adverse reactions
Nausea & vomiting
 Mechanisms
 activation of the chemoreceptor
trigger zone (CTZ) either directly
or indirectly
 peripheral stimulation of the
gastrointestinal (GI) tract
 vestibular mechanisms
 cortical mechanisms
 alterations of taste and smell.

Adverse reactions
Nausea & vomiting
 Risk factors
•prior exposure to chemotherapy
•Chronic and heavy alcohol usage
•heightened level of anxiety
during the chemotherapy infusion
•being prone to motion sickness
•severe emesis during pregnancy

Adverse reactions
Nausea & vomiting
 Pharmacologic agents
 Selective 5-HT3 antagonists
 Metoclopramide
 Corticosteroids
 Others: phenothiazines,
butyrophenones, and cannabinoids
 Adjuvants: Antianxiety agents

Adverse reactions
Nausea & vomiting
Guidelines for Antiemetic Dosing
Antiemetic Dose: Acute Dose: Delayed
Emesis Emesis
5-Hydroxytryptamine type 3 receptor
antagonists: administer once
prechemotherapy
Ondansetron 0.15 mg/kg IV or 8 mg IV 8 mg b.i.d. x 2–3 d
12–16 mg PO
Granisetron 0.01 mg/kg IV or 1 mg IV
1 mg PO
Dolasetron 1.8 mg/kg IV or 100 mg IV
100–200 mg PO
Palonosetron 0.25 mg IV

Corticosteroid High risk: 8 mg PO b.i.d. d

Dexamethasone 2–4
10–20 mg IV
Moderate risk: 4–8 mg PO
b.i.d. d 2–3
 Guidelines for Antiemetic Dosing
Antiemetic Dose: Acute Emesis Dose: Delayed
Emesis
Dopamine
antagonists

Metoclopramide 2–3 mg IV 0.5 mg/kg or 20–40 mg

prechemotherapy PO q.i.d d 2–5
Repeat 2 h
postchemotherapy
Prochlorperazine 10 mg IV or PO every
3–4 h p.r.n

Adverse reactions
Nausea & vomiting Back
 Oral Complications
 chemotherapy- and radiation
therapy–related stomatitis and
associated oropharyngeal pain
 xerostomia
 oral infection
 oral chronic graft-versus-host
disease (cGVHD)

Adverse reactions
Oral complications
 Patient Risk Factors for Stomatitis
 Age older than 65 y or younger than 20 y
 Gender
 Poor oral health and hygiene
 Periodontal diseases
 Microbial flora
 Chronic low-grade mouth infections
 Salivary gland secretory dysfunction
 Herpes simplex virus infection
 Inability to metabolize chemotherapeutic agent effectively
 Poor nutritional status
 Exposure to oral stressors such as alcohol and smoking
 Ill-fitting dental prostheses Adapted from
Barasch A, Peterson DE
1999
Dodd MJ, Miaskowski C,
Shiba GH, et al, 2003
Treatment-Related Risk Factors for
Stomatitis
 Radiation: dose, schedule
 Chemotherapy: drug, dose, schedule
 Myelosuppression
 Neutropenia
 Immunosuppression
 Reduced secretory immunoglobulin A
 Oral care during treatment
 Infections: bacterial, viral, fungal
 Use of antidepressants, opiates, antihypertensives,
antihistamines, diuretics, and sedatives
 Impairment of renal and/or hepatic function
 Protein or calorie malnutrition, and dehydration
Adapted from
 Xerostomia Barasch A, Peterson DE
1999
Dodd MJ, Miaskowski C,
Shiba GH, et al, 2003
 Chemotherapy induced
stomatitis
 40% of chemotherapy patients develop
stomatitis
 approximately 50% of these patients
develop severe painful lesions requiring
treatment modification or parenteral
analgesia
 patients undergoing BMT have high
incidence rates of stomatitis of more
than 60%
Adverse reactions
Oral complications
 Chemotherapy induced
stomatitis
 asymptomatic erythema
 progresses from solitary, white,
elevated desquamative patches
that are slightly painful to large,
contiguous, pseudomembranous,
painful lesions

Adverse reactions
Oral complications
 Graft versus Host Disease
 an alloimmune condition derived
from an immune attack mediated
by donor T cells recognizing
antigens expressed on normal
tissues
 80% of patients who have
extensive cGVHD have some sort
of oral involvement
Adverse reactions
Oral complications
 Oral cGVHD
 presents with
 tissue atrophy and erythema
 lichenoid changes (hyperkeratotic striae,
patches, plaques, and papules)
 pseudomembranous ulcerations occurring
typically on buccal and labial mucosa and
the lateral tongue, angular stomatitis
 xerostomia

Adverse reactions
Oral complications
 Prevention & Treatment
 Pretreatment oral/dental stabilization
 to eliminate sites of oral infection and
trauma
 provide adequate cleaning
 encourage appropriate oral hygiene
 Frequent oral cavity assessment is
necessary to capture clinical signs
before, during, and after the treatment
time course
 Pain management

Adverse reactions
Oral complications
 Prevention & Treatment
 Sialogogues
 Pilocarpine

side effects of glaucoma, cardiac problems, and
sweating
 Amifostine (Ethyol)
 200 mg/m2 as a 3-minute IV infusion 15 to 30
minutes before each fraction of radiation
 Oral hygiene regimens
 reduce colonization and proliferation of oral
pathogens
 water or saline

 daily fluoride application with brushing teeth at least

Adverse reactions
three times daily.
Oral complications
 Prevention & Treatment
 Direct Cytoprotectants:Sucralfate
 Not efficacious in 5FU induced or radiation
induced stomatis but patients reported less
pain
 Benzydamine
 nonsteroidal agent with analgesic,
anesthetic, antiinflammatory, and
antimicrobial properties
 efficacious for both stomatitis and radiation
therapy–induced stomatitis
 Steroid mouthwashes
 Allopurinol
Adverse reactions
Back
Oral complicatons
Acute Anthracycline
induced cardiotoxicity
 rare, but reversible
 presents as a myocarditis, with or
without pericarditis
 may result in transient congestive
heart failure (CHF)/arrhythmias

Adverse reactions
Cardiac
 Delayed Anthracycline
induced cardiotoxicity
 irreversible, dilated cardiomyopathy
 presents clinically as
 fatigue
 dyspnea on exertion
 orthopnea
 sinus tachycardia
 S3 gallop rhythm
 pedal edema/pleural effusions
 elevated jugular venous distention
Adverse reactions
Cardiac
 Risk factors for
Cardiomyopathy
 Cumulative dose
 5% risk is seen

450 mg/m2 for doxorubicin

900 mg/m2 for daunorubicin

935 mg/m2 for epirubicin

223 mg/m2 for idarubicin
 Cofactors
 mediastinal irradiation
 older (particularly older than 70 years) or younger
(younger than 15 years) age
 coronary artery disease (CAD), other valvular or
myocardial conditions
 hypertension

Adverse reactions
Cardiac
Cardiotoxicity
 Mediastinal radiation
 Drugs
 Anthracyclines

Doxorubicin
 Mitoxantrone
 Cyclophosphamide
 Ifosfamide
 Paclitaxel
 Docetaxel
 5-fluorouracil
 Monoclonal antibodies: trastuzumab
Adverse reactions
 Diagnosis
 compare baseline with serial left
ventricular function studies using
radionuclide imaging or
echocardiography, or both

Adverse reactions
Cardiac Back
 Causes of anemia in patients with cancer

• cytotoxic chemotherapy
• malignancy:
anemia of chronic disease
bone marrow involvement
• bleeding
• nutritional: iron, vitamin B12, folic acid
 Management of anemia in patients with cancer

•Determine the cause!

•Blood transfusions: packed RBC
•Recombinant human erythropoietin
Anemia secondary to chemotherapy
•Therapy with iron, and vitamins if deficien
Febrile neutropenia

Fever: one temperature > 38.5’C

or
three readings > 38’C but < 38.5’C
+ Neutropenia: ANC < 500 cells/uL
Management of patients with febrile neutropenia

Careful history and physical examination

Diagnostics
Chest Xray
Gram stain & culture of blood, urine & sputum, if any
In this patient, one blood specimen should be
drawn from intravenous catheter
Treatment
Empiric antibiotic coverage: broad spectrum with
anti-Pseudomonas activity
Modifications based on individual patient presentations
 Management of febrile neutropenia
Transfusion of granulocytes: as initial treatment, no role
•reserved for patients unresponsive to antibiotics

Colony stimulating factors

• enhance neutrophil recovery after chemotherapy,
thereby shorten the period of maximal vulnerability to
fatal infection
•adverse effects: fever, hypoxemia, pleural effusion,
Serositis
•expensive
Factors that favor low risk for severe
infection
ANC > 100 cells/mm3
Absolute monocyte count > 100 cells/mm3
Normal findings on chest radiograph
Duration of neutropenia < 7 days
Resolution of neutropenia expected in < 10 days
No intravenous catheter site infection
Factors that favor low risk for severe
infection
Early evidence of bone marrow recovery
Malignancy in remission
Peak temperature < 39’C
No appearance of illness
No abdominal pain
No neurological or mental changes
No comorbidity complications
Thrombocytopenia
 Risk of bleeding depends on the
platelet count among other factors,
like infection, mucosal breaks
 Follow guidelines for platelet
transfusion

Back
 Chemotherapeutic agents associated
with pulmonary toxicity
Chemotherapeutic Incidence
agent
Bleomycin up to 10%
Mitomycin 3–14%
Carmustine (BCNU) 20–30%
Methotrexate 2–8%
Paclitaxel 3–10% (acute
hypersensitivity)
•Rare: Busulfan,Cyclophosphamide,Chlorambucil,Melphalan,Docetaxel

Adverse reactions
Pulmonary
 Mechanisms
 direct toxic effect on alveolar
epithelial cells
 induction of an inflammatory
immunologic response
 endothelial cell injury or activation
causing capillary leak syndrome

Adverse reactions
Pulmonary
Neurotoxicity
 Vinca alkaloids
 Cisplatin , Oxaliplatin
 Thalidomide
 Cytarabine
 Ifosfamide
 Methotrexate
 Paclitaxel , docetaxel

Adverse reactions
 Vincristine Neurotoxicity
 Axonal injury with relative
preservation of the myelin sheath
 Peripheral, central or autonomic
nervous system
 most common and initial
manifestations
 depression of the deep tendon
reflexes
paresthesias of the distal extremities
Adversereactions
Neurotoxicity
 Vincristine Neurotoxicity
 Motor dysfunction and gait disorders are
initially manifested as lower extremity
weakness
 Cranial nerves may be affected and
cause ophthalmoplegia and facial palsy
 Toxicity to the parasympathetic nervous
system is manifested by constipation
and difficult micturition
 Autonomic neuropathy can also produce
orthostatic hypotension (which can be
symptomatic or clinically silent) and
erectile and ejaculatory dysfunction
Adverse reactions
Back
Hypersensitivity Reactions
 Hypersensitivity to
Taxanes
 clinical manifestations of type I
hypersensitivity reaction
 bronchospasm and wheezing, agitation,

chest and back pain, rash, angioedema, and

hypotension
 onset is usually within minutes of starting a

drug infusion
 even very small drug doses are capable of

initiating a reaction
 apparent hypersensitivity that may be delayed

in onset is pulmonary infiltrates typical of a

hypersensitivity pneumonitis that may either
resolve spontaneously or after corticosteroid
therapy
Adverse reactions
 Hypersensitivity reactions
 Paclitaxel
 Frequency : 5%
 Cremophor EL excipient used to
maintain solubility of paclitaxel
 most often (more than 70% of the
time) occur with the first drug dose
suggests a nonimmunologic
mechanism
 Docetaxel
Adverse reactions
 Prophylaxis vs.
Hypersensitivity
 Infusion over 1 to 3 hours
 Premedication with corticosteroids
and antihistamines

Adverse reactions
 Hypersensitivity reactions
 l-Asparaginase produces
hypersensitivity reactions in 10% to
20% of patients
 polypeptide of bacterial origin, displaying
multiple antigenic sites that can stimulate
production of immunoglobulin E (IgE) or
other immunoglobulins
 acute onset of wheezing, pruritus, rash,
angioedema, extremity pain, agitation, and
hypotension
Back
Adverse reactions
 Hepatotoxicity
 direct effect of either the parent
drug or a metabolite
 acute event
 serum hepatic enzymes rise as
cellular damage occurs
 fatty infiltration & cholestasis may
occur as the toxic effect
progresses.
Adverse reactions
 Antitumor Agents That Cause
Hepatotoxicity
High potential for hepatotoxicity
 L-Asparaginase
 Cytarabine
 Gemtuzumab ozogamicin
 Interferons (in high doses)
 Methotrexate (long-term therapy)
 Streptozocin
High potential for hepatotoxicity with high doses
 Busulfan
 Carmustine (BCNU)
 Cyclophosphamide
 Cytarabine
 Dactinomycin
 Methotrexate
 Mitomycin
 Antitumor Agents That Cause
Hepatotoxicity
Occasional irreversible hepatotoxicity
 Busulfan (in high doses)
 Carmustine (in high doses)
 Cytarabine
 Dacarbazine
 Gemcitabine
 Methotrexate
 Mitomycin
Isolated instances of hepatotoxicity
 Dacarbazine
 Hydroxyurea
 Interferons (in low doses)
 6-Mercaptopurine
 Pentostatin
 6-Thioguanine
 Vincristine
Causes of Enzymatic
Abnormalities
 hepatic metastases
 viral hepatitis
 drugs administered for other
therapeutic purposes (e.g.,
antiemetics)

Back
Adverse reactions
Drugs most likely to cause
enzyme abnormalities
 l-asparaginase
 carmustine in high doses
 cytarabine
 dactinomycin
 etoposide
 levamisole in combination with 5-FU
 6-mercaptopurine
 methotrexate in high doses
 streptozocin
 vincristine.

Adverse reactions
Vascular toxicity
 Veno-occlusive Disease
 thrombotic microangiopathy with
hemolytic uremic syndrome
 venous or arterial thrombosis
 vascular ischemia (involving
cerebral, myocardial, or
extremity arterial vessels)
Back
Adverse reactions
 Nephrotoxicity
 Manifestations range from rise in
creatinine level or mild proteinuria
to ARF requiring dialysis

Adverse reactions
Antitumor Agents That Cause
Nephrotoxicity
High potential for nephrotoxicity
 Aldesleukin (interleukin-2)
 Azacitidine
 Cisplatin
 Gallium nitrate
 Ifosfamide
 Methotrexate (in high doses)
 Mitomycin
 Streptozocin
Antitumor Agents That Cause
Nephrotoxicity
Azotemia without nephrotoxicity
 L-Asparaginase
 Dacarbazine
Occasional irreversible nephrotoxicity
 Cisplatin
 Fludarabine
 Ifosfamide
 Interferons
 Lomustine (CCNU)
 Mitomycin
 Pentostatin
 Streptozocin
 Cisplatin renal toxicity
 dose related
 cumulative
 manifested primarily by a decrease in
the glomerular filtration rate
 clinically approximated by increases in the
serum creatinine level and decreases in
creatinine clearance
 electrolyte abnormalities such as
hyponatremia and hypomagnesemia

Adverse reactions
 Prophylaxis for cisplatin
nephrotoxicity
 Hydration with normal saline
 high chloride level inhibits cisplatin
hydrolysis in the tubules which adds
to the nephrotoxicity protection effect
of diuresis
 Mannitol is also used to enhance
diuresis
 Monitor renal function &
electrolytes
Adverse reactions
 Pulmonary Toxicity: Clinical
Presentation
 dyspnea
 nonproductive cough or a cough
productive of small amounts of pinkish
sputum
 fever is unusual
 signs of pulmonary involvement are
minimal
 occasionally, moist rales, a pleural
friction rub, or evidence of pleural fluid
may be heard over the area of
irradiation
Adverse reactions Back
Impact of Cancer and Cancer Therapy
on the Reproductive System
Tumor Direct gonadal involvement
Reproductive tract involvement
Hypothalamic and pituitary involvement
Concern about heritability of cancer
susceptibility
Surgery Removal of gonad
Genital mutilation
Failure of emission and retrograde
ejaculation
Impotence and loss of orgasm
Impact of Cancer and Cancer Therapy
on the Reproductive System

Radiotherapy or Germ cell depletion

chemotherapy
Loss of gonadal hormones
Mutagenic changes in germ cells
Teratogenic effects on fetus
Chemotherapy Seminal transmission of drug
Radiotherapy Loss of gonadotropic hormones
(cranial)
 Gonadal dysfunction in
men
 After cytotoxic treatment, sperm count
diminishes with a time course that
depends on the sensitivities of the
different spermatogenic cells and their
kinetics of maturation to sperm
 loss of germ cells has secondary effects
on the hypothalamic-pituitary-gonadal
axis

Adverse reactions
 Gonadal dysfunction in
women
 temporary amenorrhea
 may occasionally last several years
 often a result of direct ovarian
damage, which causes loss of
maturing follicles or failure of
follicular recruitment
 alternative causes: stress,
malnutrition, or weight loss alter
hypothalamic activity and estrogen
metabolism
 age independent
Adverse reactions
 Gonadal dysfunction in
women
 permanent amenorrhea
 may begin during chemotherapy or
subsequently, after several years of
oligomenorrhea
 dramatically and continuously
increases with age at treatment

Adverse reactions
 Second cancers
 Not all second cancers are due to
therapy
 Other causes:
 host influences
 genetic susceptibility

immunodeficiency
 common carcinogenic influences
 clustering of risk factors
 diagnostic surveillance
 chance event

Adverse reactions
 Second cancers
 Radiation induced
 Leukemia
 Breast cancer
 Lung cancer
 Chemotherapy related
 AML
 Alkylating agents
 Topoisomerase II inhibitors

Back
Adverse reactions
 Radiation-Induced Nausea and
Vomiting
 related to the size of the radiation
field, the dose per fraction, and
the site of irradiation
 exact mechanism of radiation-
induced emesis remains unclear
 Central
 peripheral

Adverse reactions
Nausea & vomiting
 Radiation Therapy–Induced
Stomatitis
 universal when radiation therapy
includes the oropharyngeal area
 severity dependent on
 type of ionizing radiation
 volume of irradiated tissue
 dose per day
 cumulative dose
 duration of radiotherapy

Adverse reactions
Oral complications
 Radiation Pneumonitis
 5% to 15% of patients receiving high-
dose external-beam radiation for
treatment of lung cancer
 Factors that can add to the
development of radiation pneumonitis
 concomitant chemotherapy
 previous irradiation
 withdrawal of steroids

Adverse reactions
Pulmonary