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.
What information should be
disclosed to her when you see
her during consultation?
A. Diagnosis
B. Stage of her disease
C. Options for treatment
D. Complications of treatment
E. All of the above
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

Adverse reactions
 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
Table 54.5-3: Therapeutic Interventions in Alopecia

Decrease local delivery

Scalp tourniquet

Scalp hypothermia

Protection of the hair bulb

Topical minoxidil

AS101

-Tocopherol

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

Adverse reactions
Hair loss
 Definitions
• Nausea
• Vomiting
• Retching

Adverse reactions
Nausea & vomiting
 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
 Pathophysiology
• CTZ located in the area postrema of the brain
• can be reached by emetogenic chemicals via
the cerebrospinal fluid or the blood
• release of various neurotransmitters that
activate the vomiting center
dopamine, serotonin, histamine, norepinephrine,
apomorphine, neurotensin, angiotensin II, vasoactive
intestinal polypeptide, gastrin, vasopressin, thyrotropin-
releasing hormone, leucine-enkephalin, and substance P
• 5-hydroxytryptamine [serotonin (5-HT)]
receptors are particularly important in the
pathophysiology of acute vomiting
• others may be more important in the
pathophysiology of nausea and delayed
emesis. 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
Table 54.1-2: Guidelines for Antiemetic Dosing

Antiemetic Dose: Acute Emesis Dose: Delayed 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

Dexamethasone 10–20 mg IV High risk: 8 mg PO b.i.d. d 2–4

Moderate risk: 4–8 mg PO b.i.d. d 2–3

Dopamine antagonists

Metoclopramide 2–3 mg IV prechemotherapy 0.5 mg/kg or 20–40 mg 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
 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
 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
Table 54.2-1: Patient- and Treatment-Related Risk Factors for Stomatitis

Patient-related

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

Treatment-related

Radiation: dose, schedule

Chemotherapy: drug, dose, schedule

Myelosuppression

Neutropenia Adapted from

Barasch A, Peterson DE
Immunosuppression
1999
Reduced secretory immunoglobulin A
Dodd MJ, Miaskowski C,
Oral care during treatment Shiba GH, et al, 2003
Infections: bacterial, viral, fungal

Use of antidepressants, opiates, antihypertensives, antihistamines, diuretics, and sedatives

Impairment of renal and/or hepatic function Adverse reactions

Protein or calorie malnutrition, and dehydration
Oral complications
Xerostomia
 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
 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
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
Adverseatreactions
– daily fluoride application with brushing teeth least
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
Adverse reactions
• Allopurinol Oral complicatons
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
axilla
What particular toxicities
should he watch out for?
A. Cardiotoxicity
B. Neurotoxicity
C. Pulmonary toxicity
D. Hypersensitivity reactions
E. All of the above
 Cardiotoxicity
• Mediastinal radiation
• Drugs
– Anthracyclines
• Doxorubicin
– Mitoxantrone
– Cyclophosphamide
– Ifosfamide
– Paclitaxel
– Docetaxel
– 5-fluorouracil
• Monoclonal antibodies: trastuzumab
Adverse reactions
 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
 Diagnosis
• compare baseline with serial left
ventricular function studies using
radionuclide imaging or
echocardiography, or both

Adverse reactions
Cardiac
 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
 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
 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
 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 Adverse reactions
– paresthesias of the distal extremities
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
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
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
 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
Adverse reactions
therapy
 Prophylaxis vs.
Hypersensitivity
• Infusion over 1 to 3 hours
• Premedication with corticosteroids
and antihistamines

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
 Causes of Enzymatic
Abnormalities
• hepatic metastases
• viral hepatitis
• drugs administered for other
therapeutic purposes (e.g.,
antiemetics)

Adverse reactions
Table 54.8-3: Antitumor Agents That Cause Hepatotoxicity

High potential for hepatotoxicity

L-Asparaginase Interferons (in high doses)

Cytarabine Methotrexate (long-term therapy)

Gemtuzumab ozogamicin Streptozocin

High potential for hepatotoxicity with high doses

Busulfan Dactinomycin

Carmustine (BCNU) Methotrexate

Cyclophosphamide Mitomycin

Cytarabine

Occasional irreversible hepatotoxicity

Busulfan (in high doses) Gemcitabine

Carmustine (in high doses) Methotrexate

Cytarabine Mitomycin

Dacarbazine

Isolated instances of hepatotoxicity

Dacarbazine 6-Mercaptopurine

Chlorambucil Pentostatin

Hydroxyurea 6-Thioguanine

Interferons (in low doses) Vincristine

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
 Nephrotoxicity
• Manifestations range from rise in
creatinine level or mild proteinuria
to ARF requiring dialysis

Adverse reactions
Table 54.8-2: Antitumor Agents That Cause Nephrotoxicity

High potential for nephrotoxicity

Aldesleukin (interleukin-2) Ifosfamide

Azacitidine Methotrexate (in high doses)

Cisplatin Mitomycin

Gallium nitrate Streptozocin

Azotemia without nephrotoxicity

L-Asparaginase Dacarbazine

Occasional irreversible nephrotoxicity

Cisplatin Lomustine (CCNU)

Gallium nitrate Mitomycin

Fludarabine Pentostatin

Ifosfamide Streptozocin

Interferons

Isolated instances of nephrotoxicity

Carboplatin 6-Mercaptopurine

Gemcitabine Methotrexate (in low doses)

Adverse reactions
 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 &
Adverse reactions
electrolytes
 Vascular toxicity
• Veno-occlusive Disease
• thrombotic microangiopathy with
hemolytic uremic syndrome
• venous or arterial thrombosis
• vascular ischemia (involving
cerebral, myocardial, or extremity
arterial vessels)
Adverse reactions
 Gonadal Dysfunction
Table 54.6-1: 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

Radiotherapy or chemotherapy Germ cell depletion

Loss of gonadal hormones

Mutagenic changes in germ cells

Teratogenic effects on fetus

Chemotherapy Seminal transmission of drug

Radiotherapy (cranial) Loss of gonadotropic hormones

Adverse reactions
 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
Adverse reactions
– age independent
 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
Adverse reactions