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Toxicities of targeted therapies
1. Toxicities Of Targeted
Therapies
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Md medical oncology
L/O/G/O
www.themegallery.com
2. Targeted Therapy in Oncology
Def: A drug with a focused mechanism that
specifically acts on a well-defined target or
biologic pathway that, when inactivated,
causes regression or destruction of the
malignant process.
3. Features of the Ideal Anticancer Target
Crucial to the malignant phenotype.
Not significantly expressed in vital organs and tissues.
A biologically relevant molecular feature.
Reproducibly measurable in readily obtained clinical
samples.
Correlated with clinical outcome.
Clinical response in a significant proportion of patients
whose tumors express the target when target interrupted,
interfered with, or inhibited.
Minimal responses in patients whose tumors do not express
the target.
6. Cardiac toxicity may be
• The on target effect : is caused by a
target promoting both cancer cell growth
and cardiomyocyte function.
• The off target effect : instead, occurs
when a TKI causes an inhibition of a
“bystander” target (i.e. a target not
essential to kill cancer cells but involved in
cardiomyocyte survival).
8. 1- Hypertension
Most common with drugs targeting
angiogenesis through the vascular
endothelial growth factor (VEGF) and/or its
receptor (VEGFR) pathway:
• Monoclonal antibodies that bind the VEGF ligand (i.e.
bevacizumab),
• Decoy VEGF receptors (i.e. aflibercept), and
• Small-molecule tyrosine kinase inhibitors of VEGFR
(i.e. sorafenib, sunitinib).
Vascular disrupting agents (VDAs) they disrupt the
established abnormal vasculature that feeds tumors
(exception ) not inhibit VEGF.
9. Mechanisms of hypertension of
antiangiogenesis drugs:
1-VEGF is known to increase the synthesis of nitric oxide, a
vasodilator, through upregulation of endothelial nitric
oxide synthase. Anti-VEGF agents therefore decrease
levels of endogenous nitric oxide n blood vessel walls,
resulting in vasoconstriction and increased blood
pressure.
2- VEGF inhibition also up-regulates baroreceptor
function, increasing vascular tone.
3-Reduction in the number of arterioles and capillaries,
which contributes to vascular stiffness and increased
peripheral vascular resistance (rarefaction).
4 -Decreased sodium ion renal excretion and thus
increased cardiac afterload.
12. Evaluation of hypertension
1. Criteria for definition of hypertension:
single gross elevation in blood pressure
which is symptomatic (hypertensive
urgency/emergency).
serial measurement of abnormal
elevations of either systolic or diastolic
blood pressure.
14. NCI-CTCAE version 3.0 grades of HTN
Adverse event Definition
Grade 1 Asymptomatic, transient increase; no treatment
required
Grade 2 Recurrent, persistent or symptomatic increase;
monotherapy may be required
Grade 3 Requiring more than one drug or more intensive
therapy than previously
Grade 4 Life-threatening (e.g. hypertensive crisis)
15. 2. Careful baseline assessment of cardiovascular risk is
performed
3. patients with significant cardiovascular
disease within 6 to 12 months of anti-VEGF treatment
initiation were generally excluded.
4- Comprehensive history and physical, as well as directed
laboratory, investigations are also mandatory for
cardiovascular risk stratification.
5- Individualised risk benefit analysis is recommended ,
patients who are at very high risk pre-treatment
would have been excluded from the anti-angiogenic
clinical trials.
16.
17. 6- Current target blood pressure goals for cancer patients being
considered for and receiving antiangiogenics:
• <140/90 mmHg
• <130/80 mmHg in diabetic and chronic renal dysfunction
populations.
7- Once on therapy, it is imperative that regular and
comprehensive blood pressure monitoring occurs, with
initiation of anti-hypertensive agents if blood pressure
crosses accepted thresholds.
8- Clinical practice guidelines recommend blood pressure
monitoring weekly during the first cycle of therapy, and then at
least every 2 to 3 weeks for the duration of anti-VEGF drug
exposure
18. • Interestingly, there is a growing belief that
hypertension may act as a valuable
biomarker of efficacy with anti-VEGF
agents.
• This was found with bevacizumab, axitinib
and sorafenib and needs to proved in
more prospective trials.
20. A- non-pharmacologic interventions
• avoid excessive alcohol consumption and
excessive salt intake ,
• Avoidance of other aggravating drugs
such as non-steroidal anti-inflammatory
drugs, steroids, erythropoietin agonists
and sympathomimetics is also
recommended when clinically feasible
21. B- Pharmacologic management
There is no consensus on recommendations
of specific antihypertensive regimens used
to manage HTN related to angiogenesis
antagonists.
Treatment recommendations should be
made on the basis of the potential risks
and benefits associated with each unique
drug and patient.
22. USE of ACE (angiotensin-converting enzyme)
inhibitors may be beneficial as they affect nitric
oxide.
The American Diabetes Association recommends
use of angiotensin-receptor blockers as the
treatment of choice in hypertensive patients with
diabetes, frank proteinuria, and/or
microalbuminuria.
Sunitinib: Diuretics remain the first-line choice for
treatment of HTN in all patient populations,
except those with chronic kidney disease (CRD).
Application of the general guidelines
23.
24. C- Modification of the anti-VEGF agent
dose or schedule.
• Depending on the type of anti-VEGF agent For
patients receiving daily-dosed tyrosine kinase
inhibitors of VEGF such as sunitinib or sorafenib,
temporarily withholding or reducing the drug can be
rapidly effective if hypertension is symptomatic or
refractory to standard anti-hypertensive interventions.
• Anti-VEGF agents with longer half-lives such as
bevacizumab and aflibercept do not respond as quickly
to withdrawal or dose reduction. So:
• Do not start if ( systolic >160mmHg and diastolic
>100mmHg), Aggressive anti-hypertensive efforts before
ttt , close monitoring, if failed refer to hypertensive
expert.
26. Pathogenesis:
• Myocardial cells have limited regenerative capacity,
which renders the heart susceptible to transient as well
as permanent drug effects
• Drug-induced ventricular dysfunction can occur via
several distinct mechanisms:
Type I cardiotoxicity, as caused by anthracyclines, results in
structural abnormalities of the cardiac ultrastructure and subsequent
cell death and clinical heart failure.
Type II cardiotoxicity ( induced by molecularly targeted agents
(particularly trastuzumab) is caused by failure of myofibril contractile
elements to exert coordinated activity, but cell death and clinical
heart failure are not dominant features and is more likely to be
reversible.
27. PATHOGENESIS of Trastuzumab
cardiotoxicity
• Targeting ErbB2 (human epidermal growth
factor type 2 / Her2) which has a role in
normal myocyte function
• Induces mitochondrial apoptosis. Mitochondria are
essential for myocyte vitality, as they generate
adenosine triphosphate (ATP), the “fuel” for muscle
contractility and survival.
It is possible that antibody dependent, cell-mediated
cytotoxicity is a substantial contributor to impaired ErbB2
function in myocytes, although this hypothesis remains
theoretical and has not been scientifically substantiated.
28. Trastuzumab cardiotoxicity:
Incidence :
• In metastatic breast, trastuzumab administered in combination with
anthracycline-based combination chemotherapy demonstrated a
surprising 27% cardiotoxicity rate,versus 13% with chemotherapy
alone.
• Adjuvant breast cancer trastuzumab trials indicates that grade
3 or 4 cardiac toxicity occurred in 4.5% of patients receiving
trastuzumab versus 1.8% in women who did not receive the drug.
Risk factors:
older age, concurrent administration chemotherapy or exposure to
previous anthracyclines, baseline left ventricular dysfunction,
coronary artery disease, uncontrolled hypertension, valvular heart
disease, and cardiac arrhythmia. Non-cardiovascular risk factors
may include chest wall radiation, diabetes and obesity .
Ventricular recovery is variable, ranging from 1.5 months to 1.5
years, rechallenge after ventricular recovery is well
documented
29. Cardiotoxicity associated with other
molecularly targeted agents
• Lapatinib: low levels of cardiac toxicity of
• 1.5−2.2%, almost always reversible, and almost always
asymptomatic.
• Sunitinib: mechanism uncertain, HF rate 2.7% to 11% with
41% recovered. left-ventricular ejection monitoring, be incorporated
into standard practice for patients receiving sunitinib.
• Imatinib: Severe congestive heart failure and left ventricular
dysfunction have occasionally been reported in patients treated with
imatinib. Patients with cardiac disease or risk factors for cardiac failure
should be monitored carefully and any patient with signs or
symptoms consistent with cardiac failure should be evaluated and treated
• Bevacizumab and Alemtuzumab
30. An oncologist’s approach to ventricular
dysfunction
1. Baseline assessment of their LVEF.
2. Only patients with normal cardiac function and
no symptoms of congestive heart failure as
quantified by the New York Heart Association
(NYHA) classification system should be treated
with a potentially ventricular-toxic agent.
3. Regular monitoring with physical examination
as well as radiological measurement of left
ventricular ejection fraction should ensue.
4. Any symptoms or signs suggestive of heart
failure, functional cardiac assessment should
occur.
31.
32. MANAGEMENT
Once significant cardiac dysfunction is demonstrated,
molecularly targeted therapy should be interrupted and
aggressive management of heart failure should be
implemented.
• No specific strategy, so general population guidelines
should be followed.
• Serial reassessment of cardiac status is needed once
dysfunction is demonstrated, rechallenge was tolerable
with trastuzumab but follow-up is immature.
34. Background and mechanisms of QT
prolongation
• On the ECG, the QT
interval is measured
from the beginning of
the QRS complex to
the end of the T wave
in the lead without
prominent U waves.
35. • The QT interval on the ECG is a measure of ventricular
depolarisation and repolarisation, corresponding to the
duration of the ventricular action potential.
• The interval is known to have biologic variation, most
importantly with gender and heart rate. Formulae exist to
account for these biologic confounders, and “corrected”
QT (QTc) measurements of 450ms for men and 470ms
for women are generally accepted as the upper limit of
normal.
• Ventricular arrhythmias, particularly torsade de pointes
(TdP), correlate with a QTc interval of more than 500ms
39. • The FDA has provided specific safety guidelines
for QTc interval monitoring with arsenic trioxide
administration (applicable when using other drugs):
All patients must demonstrate a baseline QTc (best
determined as a mean of three electrocardiograms
more than 5 minutes apart) less than 500 ms, as well
as maintain serum potassium greater than 4 mEq/L
and magnesium greater than 1.8 mg/dL.
If the QTc interval is greater than 500 ms or symptoms
of syncope or palpitation occur, electrolyte
replenishment and immediate hospitalization are
advised, with cessation of arsenic trioxide treatment
until QTc less than 460 ms.
41. • Bevacizumab :
A. Arterial thromboembolic events (ATEs):
• Included cerebral infarction, transient ischemic attacks
(TIAs), myocardial infarction (MI), and angina.
• More frequently (4.4 versus 1.9%) and were more often
fatal (0.7 versus 0.4%) in patients receiving
bevacizumab in combination with chemotherapy
compared with those receiving chemotherapy alone.
• There is an increased risk of any ATE in bevacizumab-
treated patients who have a prior history of stroke/heart
attack (~5 fold), in those aged 65 years (~3 fold) and in
patients with hypertension (~2 fold). Bevacizumab
should be permanently discontinued in patients who
develop ATEs.
42. • Bevacizumab :
B . Venous thromboembolic events (VTEs):
• Include deep venous thrombosis, pulmonary embolism
and thrombophlebitis.
• VTEs occurred more often in patients receiving
bevacizumab with chemotherapy than in those receiving
chemotherapy alone.
• If any grade 3-4 VTE occurs in a clinical trial, dosing
with bevacizumab should be stopped for 3 weeks.
Administration should only be continued when
anticoagulation parameters have stabilised. Patients with
symptomatic pulmonary embolism must not be treated
with bevacizumab
43. • IMMUNOMODULATORY AGENTS
Thalidomide and Lenalidomide use is
associated with significantly increased
incidence of deep venous thrombosis.
Prophylactic anticoagulation is
recommended during therapy of either
drug.
45. • Skin Toxicity Of Epidermal growth
factor receptor (EGFR) inhibitors.
• Skin Toxicity Of Multikinase inhibitors
(sorafenib, sunitinib,imatinib)
46. • Skin Toxicity Of Epidermal growth
factor receptor (EGFR) inhibitors.
• Skin Toxicity Of Multikinase inhibitors
(sorafenib, sunitinib,imatinib)
47. Epidermal growth factor receptor (EGFR)
inhibitors
• EGFR targeted drugs consist of monoclonal antibodies
to EGFR (e.g. cetuximab, panitumumab),
• small-molecule tyrosine kinase inhibitors specific for
EGFR (e.g. erlotinib, gefitinib),
• dual kinase inhibitors inhibiting EGFR and HER2
(lapatinib),
• pan-erbB inhibitors inhibiting EGFR and other erbB
receptors (canertinib)
• and other less specific inhibitors such as vandetanib
inhibiting EGFR, vascular endothelial growth factor
receptor (VEGFR) and RET.
48. Clinical picture
• Probably owing to the abundant expression of
EGFR in the epidermis and its appendages (hair
follic.
• EGFR-inhibitor-induced skin toxicity consists
of : an acneiform eruption, skin dryness
leading to eczema and fissures, nail changes,
hair changes, telangiectasia,
hyperpigmentation and mucosal changesles,
sebaceous glands)
50. • The most frequently reported side effect of EGFR
inhibitors is a dose-dependent acneiform eruption,
occurring in 50% to 100% of patients.
• The eruption is more or less confined to the
seborrheic areas (rich in sebaceous glands): the
face (especially the nose, the cheeks, the forehead
and the chin), the scalp, the neck and retroauricular
area,the shoulders and the upper trunk (typically V-
shaped).
The eruption tends to be more severe and
widespread with monoclonal antibodies than with
oral tyrosine kinase inhibitors (for which gastro-
intestinal toxicity is a dose-limiting factor)
51. • The skin lesions consist of sometimes itchy,
erythematous follicular papules that may evolve into
pustules.
• The papulopustular eruption can appear just a few days
(2−3 days for biologics, 7−10 days for small molecules)
after treatment with the EGFR inhibitor, often reaching a
maximum 2 to 3 weeks following initiation of therapy.
• Slow spontaneous improvement of the rash is the rule
when the EGFR inhibitor is continued even in the
absence of dermatologic supportive treatment .
52. • Flare up of the rash can occur following each
infusion (in the case of intravenously
administered monoclonal antibodies) and Sun
exposure .
• Acneiform eruption by EGFR inhibitors is
essentially sterile but superinfection with
Staphylococcus aureus may occur.
• Skin areas that previously underwent
radiotherapy are characteristically spared from
the acneiform eruption. Concomitant cetuximab
and radiotherapy on the other hand appear to
increase the incidence of severe radiodermitis.
53. EGFR-inhibitor-induced rash is acneiform should
clearly be distinguished from acne vulgaris: indeed,
comedones (blackheads and whiteheads) − the hallmark
of true acne are lacking and so are nodules.
Moreover, itchiness is not infrequent in EGFR inhibitor-
induced acneiform but is absent in acne vulgaris. Finally,
scalp involvement is rare in acne but frequent in
patients receiving EGFR inhibitors.
55. • EGFR inhibitors often gradually develop a dry
skin over weeks.
• Old patient age, previous therapy with cytotoxics
and a history of atopic eczema will accentuate
the cutaneous dryness, which manifests with
dry, scaly, itchy skin.
• The xerosis may develop into chronic asteatotic
eczema
• secondary infection
• Painful fissures
56. Nail changes
• In 10−15% of patients, do
not start earlier than 4−8
weeks after the initiation
of the EGFR inhibitor
• Paronychia very painful
inflammation of the nail
fold. (caused by
epidermal cell growth
arrest and differentiation
• Induced by the EGFR
inhibitor)
57. Hair changes
• Very characteristic
are the long, curly, rigid
eyelashes, termed
Trichomegaly
• The eyebrows
become thicker and
more rigid as well,
with lateral thinning.
• Slow growth of scalp
hair,and beard.
58. Other skin toxicities
• Telangiectasia
• The telangiectasia together with facial
erythema, tenderness and follicular papulopustules
in the absence of comedones creates a rosacea-like
picture of the face. Unlike other telangiectasia, the
lesions tend to fade over months usually leaving some
hyperpigmentation
• Hyperpigmentation
• Mucosal changes:
Conjunctivitis,.
Dry mouth, apthous stomatitis.
dry vulvovaginitis (especially in postmenopauzal (women) or
balanitis.
60. General measures and treatment
principles
• Adequate sun protective measures
• avoid skin care products that dry out the skin
• An emollient/hand cream can be used on the limbs and
hands to prevent xerosis and fissures
• Prophylactic treatment of acneiform eruption, as it occurs
in 80% of patients on EGFR inhibitors:
Minocycline 100 mg qd , oral tetracycline 500 mg bid and a
regimen consisting of doxycycline 100 mg bid,
topical hydrocortisone 1%, emollients and a sunscreen
decreased severity of acneiform eruption.
61. Treatment of acneiform eruption
• Topical metronidazole and oral
minocycline are the standard of treatment.
• As a topical therapy, metronidazole is preferred
(as a 2% preparation in cetomacrogol cream or
as 0.75% Rozex® cream) because of its
mildness, as it is normally used for the very
sensitive skin of rosacea patients, twice a day or
in between as needed on the first appearance of
papulopustular lesions
62. • Topical retinoids (adapalene, tazarotene) are
used by some but lack rationale.
• Acneiform eruption-associated itchiness can
easily be controlled with an oral antihistaminic.
• Calcineurin antagonists (tacrolimus or
pimecrolimus), being used as first-line therapy in
some American centres(irritant ,expensive)
• Topical menadione (vitamin K3, an EGFR
phosphatase inhibitor with promising
• preclinical properties), not yet available for
clinical use
63. • Despite its efficacy for EGFR inhibitor-dependent
rash, oral isotretinoin should not be used as it may
possibly interfere with EGFR-inhibitor antitumor activity
by down regulating EGFR expression.
Moreover, isotretinoin shares a large number of side effects
with EGFR inhibitors (xerosis, sensitivity for S. aureus
superinfection, paronychia, pyogenic granuloma), which
may lower tolerability.
• Systemic steroids are also to be avoided in the
treatment of acneiform eruption as they may induce a
similar eruption themselves; in addition, they may
hamper the antibody-dependent cell-mediated
cytotoxicity that is ascribed to EGFR-antibodies
64. Treatment of xerosis, eczema and fissures
• Hydrating measures oil in water creams (e.g.
metronidazole cream) On the limbs, greasy (water in oil)
creams or even ointments can be used for moderate to
severe xerosis.
• Eczema :a topical weak to medium strength corticosteroid
cream is recommended for a short term (1 to 2 weeks).
• Salicylic acid : fingertip eczema.
• Infection :Treatment with topical (e.g. fusidic acid) or, in
severe cases, systemic anti-S. aureus antibiotics can be
added for 5−10 days.
• Fissures: propyleneglycol 50% aqueous solution under
plastic occlusion/salicylic acid 10% ointment, a
hydrocolloid dressing or liquid cyanoacrylate glue
65. Treatment of paronychia
Antiseptic (e.g. chloramine, polyvidon iodine)
oaks or creams are advised on a daily basis.
When superinfection is suspected, swabs can
be taken and oral anti-S. aureus antibiotics (e.g.
flucloxacillin) given anti-yeast (e.g. nystatin) and
a potent topical corticosteroid. Oral nonsteroidal
anti-inflammatory drugs can be administered
to control the pain. Silver nitrate application on a
weekly basis improves pyogenic granuloma
66. Treatment of hair changes, hyperpigmentation and
telangiectasia
• Eyelashes : laser epilation.
• Telangiectasia : electrocoagulation or pulsed dye laser
therapy.
• Treatment of mucosal changes:
• Eye : attificial tears, topical steroids,antibiotic
• Tetracycline or antiseptic mouthwash alleviates
• stomatitis symptoms. For aphtous ulcers of the
mouth,topical steroids or anaesthetics can be used.
• Dryness of the nose or the vagina responds fairly well
to lubricants or ointments containing an antibiotic or
antiseptic.
67. Associations with outcome of therapy,
predictive role
Most of the published data have shown that patients in
whom skin toxicity develops show a higher response
rate than those without rash and significant
correlations between occurrence of rash and
increased survival have been found, with a trend
towards improved overall survival and longer
progression-free survival with increasing severity of
rash.
• Some research groups state that the rash is a surrogate
indicator of an adequate degree of receptor saturation by
EGFRI.
68. • Skin Toxicity Of Epidermal growth factor
receptor (EGFR) inhibitors.
• Skin Toxicity Of Multikinase inhibitors
(sorafenib, sunitinib,imatinib)
69. Clinical picture
Sorafenib (34%) and sunitinib (19%) may
cause
1-hand-foot skin reactions (HFSR)
• Dose-dependent.
• Very characteristically localised to skin areas of friction
or pressure.
• It emerges in the first 2−3 weeks of treatment as sharply
demarcated, erythematous, painful, oedematous and
blistering lesions that evolve into extremely tender,
inflamed calluses
70.
71. 2- Asymptomatic subungual splinter haemorrhages
are seen in not less than 40−70% of patients on sorafenib or sunitinib.
Sensitivity of subungual capillaries to microtrauma due to inhibition of
VEGFR (with impaired angiogenesis) may be involved in its
pathogenesis.
3- Dryness of the skin and/or mucous membranes
(occasionally with stomatitis) are present in approximately
25% of patients receiving sorafenib/sunitinib.
4 . In the first weeks of treatment, sorafenib (and
more rarely sunitinib) may cause a sometimes flaky erythema of the
scalp and the face sparing the periorbital area, temporary alopecia, a
transient dysaesthesia of the scalp skin with a burning and painful
sensation, transient maculopapular rash.
5- Sunitinib: a yellow skin discolouring, caused by accumulation of this
yellow molecule in the integument, reversible hair depigmentation,
facialoedema.
72. • Various skin reactions have been
described with Imatinib:
• A dose-dependent, periorbital, facial or even generalised
oedema, appearing 2 weeks after starting the drug with very
gradual regression later on.
• Maculopapular eruptions (and, rarely, even more
severe drug reactions such as vasculitis, acute generalised
exanthematous pustulosis or toxic epidermal necrolysis
necessitating permanent drug withdrawal).
• Skin depigmentation but seldom also a paradoxical
hyperpigmentation (especially of the nails) or repigmentation
of grey hair.
• Xerosis cutis and pruritus.
73. Treatment and clinical management
• To minimise the impact of hand-foot skin reaction: avoid drying
of the skin; avoid friction and wear comfortable fitting clothes and
shoes; treat pre-existing calluses or hyperkeratoses or mild hand-
foot skin reaction with urea- or salicylic acid ointment.
• Moderate HFSR: ultrapotent topical steroids and topical lidocaine
to control the pain. Oral analgetics can be added accordingly.
• For severe reactions, a (temporary) dose adjustment or
interruption of the multikinase inhibitor is proposed when supportive
dermalogic treatment offers insufficient relief.
• Xerosis cutis: emollients and sometimes oral antihistamines.
• The seborrheic dermatitis-like facial lesions respond well to topical
• ketoconazole or weak steroids.
• For the maculopapular eruption with sorafenib or imatinib, topical or
systemic steroids and sometimes interruption of the drug are
advised
75. Classification
A. Nephron structure damage
Glomerular lesions
Glomerulonephritis and proteinuria
Tubular lesions
Fanconi syndrome or renal tubular acidosis
Distal tubular alteration
Interstitial lesions
Allergic interstitial nephritis
B. Vascular lesions
Renal thrombotic microangiopathy
76. Glomerulonephritis and proteinuria
• Most of the toxicity is related to anti-VEGF
• In the kidney, VEGF maintains the glomerular
and peritubular capillary network. Use of an anti-
VEGF agent may therefore disturb this network
of blood vessels, leading to glomerular
dysfunction and proteinuria.(altered glomerular
permeability).
• VEGF can act as a survival factor for podocytes
and thereby prevent glomerulonephritis
77. Glomerulonephritis
• Different types of glomerulonephritis have
been described during the use of
molecular targeted therapies including:
• membranoproliferative
glomerulonephritis ,
• minimal change disease,
• cryoglobulinemic glomerulonephritis
and focal segmental glomerulosclerosis.
79. Proteinuria:
Bevacizumab 21- 41% low dose G3
22- 63% high dose
VEGF TKIs Proteinuria and HTN
Oedema as a direct consequence of
proteinuria (it is one of the
dose-limiting toxicities of sunitinib)
MTOR inhibitors •increase in glomerular capillary
pressure or directly by increasing
Temsirolimus, sirolimus glomerular permeability/ injury.
•Podocyte injury and focal segmental
glomerulosclerosis
80. Proteinuria should be monitored in patients
receiving anti-VEGF therapy using the urine
protein to creatinine ratio.
• This index of proteinuria is commonly used in
the nephrology literature and correlates well with
24-h protein excretion.
• Dipstick values 2 or higher should be confirmed
by the ratio of urine protein to creatinine or 24-h
collection.
• Bevacizumab therapy It is known that under this
medication treatment should be interrupted in
patients with proteinuria greater than 2 g/24 h
81. Tubular lesions
1. Fanconi syndrome or renal tubular acidosis
• imatinib : failure to reabsorp bicarbonate , and to
secrete acid . Dysfunction of the proximal tubular cells
and with phosphaturia, glycosuria, aminoaciduria,
uricosuria and tubular proteinuria The principal feature of
Fanconi’s syndrome is bone demineralisation due to
phosphate wasting. This syndrome has been reported
with different TKIs like imatinib
82. 2. Distal tubular alteration
This alteration is characterised by hypomagnesaemia.
This phenomenon is one of the most frequent toxicities
described with antibodies against EGFR.
• Low Mg2+ inhibits endothelial migration and
proliferation, late events absolutely required for the
formation of new vessels, by desensitising endothelial
cells to the effects of angiogenic factors.
• The interaction between anti-EGFR agents and
Mg2+ homeostasis could be partially responsible for
the anticancer activity of these agents.
• During anti-EGFR antibodies therapy, in addition to
baseline assesment, serum Mg2+ level should be
measured when fatigue or hypocalcaemia is
encountered, and repleted as necessary
83. Interstitial lesions
• Common types of tubulointerstitial injury that can
occur secondary to therapeutic agents include
allergic interstitial nephritis, acute tubular
necrosis, crystal nephropathy, tubular atrophy,
and interstitial fibrosis
• Allergic interstitial nephritis:
Bevacizumab,sunitinib , progressive kidney
dysfunction with proteinuria, together with
peripheral eosinophilia and eosinophiluria, fever
and rash
Ttt : corticosteroids
84. Vascular lesions
• Renal thrombotic microangiopathy
sirolimus, bevacizumab, sunitinib
• Usually, withdrawal of the causing drug results in
complete recovery or at least significant
improvement of hypertension and renal
involvement.
• But, as limited therapeutic options, the
alternative of maintaining treatment while
blocking the renin–angiotensin system could be
a good strategy for hypertension and proteinuria
control
85. • Combinations and interactions with
other neprohotoxic drugs
• Most of the experience of targeted
therapies in combination with
chemotherapy has been gained with
bevacizumab and cetuximab no increase
in toxicity was found .
90. Incidence, clinical pattern and
pathophysiology of diarrhoea
1. Anti-epidermal growth factor receptor (EGFR) therapies
• Appears withen 2 weeks after treatment initiation .
• Correlated with the dose not plasma conc.
• Mechanism :
1. EGFR are widely expressed in the normal colic mucosa in
which they regulate both chloride secretion and sodium
absorption by colonocytes . Therefore, EGFR
inhibition can subsequently lead to secretory diarrhoea.
2. is also described to be involved in the maintenance of mucosal
integrity. the stimulation of mucin production and the enhancement
of prostaglandin synthesis.
4. Inhibition of EGFR might therefore lead to digestive lesions.
91. Diarrhoea occurs in about 20−28% of patients
undergoing anti-EGFR monoclonal antibody
therapy but is rarely severe: 1−2% of grade 3−4.
The incidence and severity of diarrhoea is higher
with EGFR-TKIs than with anti-EGFR
monoclonal antibodies, which have an incidence
of 50−60% including 5% grade 3−4; diarrhoea is
a dose limiting toxicity for TKIs.
• Diarrhoea related to drug toxicity was also
correlated in some studies with a clinical benefit
and/or was a predictive factor of tumour
response to TKI
92. 2. Anti-HER2 (ErbB2) therapies
• Trastuzumab is rarely associated with diarrhoea, with a
total incidence of 7% without any grade 3−4 toxicity.
• Lapatinib : diarrhoea occurred in 55% of lapatinib-
treated patients versus 24% of controls, grade 3
occurred in 9%.
• 40% of patients had the first episode of diarrhoea within
6 days after drug introduction for a median duration was
of 7−9 days.
• Diarrhoea was dose related and not associated with
serum concentration.
93. 3. Multi-targeted kinase inhibitors
• Imatinib: 40% of patients, less than 5%, grade
3−4 diarrhoea.
• The mechanism remains unknown, but one
hypothesis is the inhibition of the colonic pace-
maker cell (Cajal cells) which are c-Kit positive.
• Sunitinib :D 20% of treated patients including
3% with grade 3 but no grade 4 diarrhoea.
• Sorafenib: 39% of patients, 8% grade 3 and no grade
4. Diarrhoea was the most frequent adverse event that
led to dose reduction (8% of cases)
94. • Nilotinib: D in less than 10% of patients with only 1%
grade 3−4.
• Dasatinib : all grades of diarrhoea
• in about 50% of patients, including 6% of grade 3−4.
4. Anti-angiogenic therapies:
• Bevacizumab: diarrhoea occurred in only 12% of
patients with no grade 3 or 4 diarrhoea.
5.Others
• Temsirolimus: 27% of patients with less than 1% grade
3−4.
• Bortezomib: all grades 30−40% grade 3 4−8% , no grade 4
diarrhoea. watery, with no bleeding, and associated with mild to
moderate abdominal pain and cramps. Symptoms occur within the
first 12−18 h after infusion initiation, and lasts for 1−2 days
95.
96. Management of diarrhoea in patients
undergoing targeted therapy
1. It is important to exclude another cause of diarrhoea to avoid
inappropriate treatment discontinuation. Exclude concomitant
intake of laxative treatment, a past history of gastrointestinal tract
surgery or look forClostridium or another infection.
• 2. In most patients, diarrhoea resolves with conventional
approaches, without dose modification It can be useful to rapidly
start loperamide treatment with the classic administration of two 2
mg tablets after the first occurrence of diarrhoea followed by one
tablet after consecutive episodes every 4 h.
3. In a minority of patients (<5% of cases), but particularly with orally
administered small molecules, dose modification or treatment
discontinuation is necessary .
97. 4. If diarrhoea does not respond to limited
intervariations, a dose of 0.5 mg subcutaneously
(s.c.) of octreotide acetate every 8 h for 48−96 h
may be recommended when diarrhoea is
resistant to loperamide. Octreotide should be
discontinued within 24 hours after the resolution
of diarrhoea.
5- Severe diarrhea : hospitalisation for evaluation,
intravenous fluid administration and electrolyte
correction and/or antibiotics
99. • Wound-healing complications
• Angiogenesis is one critical mechanism in the complex process of
wound healing and bevacizumab, as an anti-angiogenic agent, has
the potential to disrupt wound healing.
• Bevacizumab is also associated with wound-healing
complications in about 2−4.5% of patients who had
surgery after treatment initiation.
• Since the half-life of bevacizumab is approximately
21 days, it is recommended that therapy should not be
initiated for at least 28 days following major surgery or
until the wound is fully healed.
• Furthermore, bevacizumab should be withheld 28−42
days before elective surgery.
100. Gastrointestinal perforations
• GI perforation (i.e., GI perforation, fistula formation,
and/or intra-abdominal abscess), occurred in 2.4% of
patients receiving bevacizumab alone or in combination
with chemotherapy in 3 clinical trials for metastatic
colorectal cancer.
• life-threatening condition,fatal in 30% of cases.
• Manifestations of these adverse GI effects included
abdominal pain with constipation and vomiting (emesis).
• The mechanism unknown. may be due to the
shrinkage of tumour masses embedded in the intestinal
wall, or may occur at the site of previous surgery. Other
risk, factors include abscesses, diverticula or an
inflammatory process involving the GI tract
101. Gastrointestinal bleeding
• Bevacizumab: Severe or fatal hemorrhages,
including hemoptysis, GI bleeding, hematemesis, CNS
hemorrhage, epistaxis, and vaginal bleeding, occurred
up to fivefold more frequently in patients receiving
bevacizumab and chemotherapy than in those receiving
chemotherapy alone.
• sorafenib : was not associated with digestive
haemorrhage or variceal bleeding in cirrhotic patients
treated for hepatocellular carcinoma.
• Imatinib, at a high dose of 800 mg/d was
responsible for digestive haemorrhage-related
death in four patients
102. Targeted therapy and hepatic
toxicity
• Kit and PDGFR inhibitors
Imatinib
Sunitinib
• Anti- EGRF :
Gefitinib
Erlotinib
Anti HER2:
Lapatinib (rare reversible)
Anti VEGF :
Bevacizumab (sclerosing cholangitis)
103. Imatinib hepatic toxicity
• In clinical trials, severe hepatotoxicity occurs in less than
5% of patients.
• To date, a total of 24 case reports of severe
hepatitisinduced by imatinib have been published.
• Little is known about the mechanisms of liver
toxicity but imatinib is metabolised by cytochrome
P450. Therefore, an increase in toxic metabolites is
possible in cases where there is use of enzymatic
Inducers.
• Also An idiosyncratic mechanism and an immuno-
allergic mechanism were probable.
104. Liver tests and prothrombin time should be
performed before initiation of imatinib and then
weekly or twice a month in the first month and
then monthly thereafter or in case of symptoms.
• Treatment has to be withdrawn in cases of
grade-3 hepatotoxicity. Some authors have re-
introduced imatinib at slowly increasing doses
together with prednisone without recurrence of
liver injury,, others suggest to modify the
schema of treatment administration
105. In conclusion, little is known about the mechanisms
of hepatotoxicity due to targeted agents and management
is often empirical.
One should be cautious with the use of enzymatic inducers or inhibitors
together with agents metabolised by the cytochrome pathway
(e.g. imatinib, gefitinib, erlotinib).
Hepatic function tests should be performed regularly . In case of liver
dysfunction, other aetiologies should be ruled out and the use of
the adverse drug reaction probability scale will help to evaluate the
relationship between drug and hepatotoxicity.
106. Elevation of pancreatic
enzymes
Elevation of lipase can be observed with the
small oral multi-targeted therapies
sorafenib, sunitinib and nilotinib.
108. Side effects and organ toxicity of protein
kinase inhibitors observed in clinical
studies.
109.
110.
111.
112. Take home message
• Although novel, molecular targeted
therapies are starting to fulfil their promise,
changing how patients with cancer are
treated and altering the natural history of
many types of cancer, they are far from
being a “magic bullet.”
