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Toxicities Of Targeted Therapies R as h a H ag gag Md medical oncology L/O/G/O www.themegallery.com
Targeted Therapy in OncologyDef: A drug with a focused mechanism thatspecifically acts on a well-defined target orbiologic pathway that, when inactivated,causes regression or destruction of themalignant process.
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 clinicalsamples. Correlated with clinical outcome. Clinical response in a significant proportion of patientswhose tumors express the target when target interrupted,interfered with, or inhibited.Minimal responses in patients whose tumors do not expressthe target.
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).
1- HypertensionMost 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.
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.
Anti-VEGF agents reporting significanthypertension in clinical trials
Evaluation of hypertension1. 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.
WHO/ISH definition and classification of bloodpressure levels 110
NCI-CTCAE version 3.0 grades of HTNAdverse event DefinitionGrade 1 Asymptomatic, transient increase; no treatment requiredGrade 2 Recurrent, persistent or symptomatic increase; monotherapy may be requiredGrade 3 Requiring more than one drug or more intensive therapy than previouslyGrade 4 Life-threatening (e.g. hypertensive crisis)
2. Careful baseline assessment of cardiovascular risk is performed3. patients with significant cardiovasculardisease 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.
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 andcomprehensive blood pressure monitoring occurs, withinitiation of anti-hypertensive agents if blood pressurecrosses accepted thresholds.8- Clinical practice guidelines recommend blood pressuremonitoring weekly during the first cycle of therapy, and then at least every 2 to 3 weeks for the duration of anti-VEGF drug exposure
• 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.
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
B- Pharmacologic managementThere 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.
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
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.
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.
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.
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
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 orsymptoms consistent with cardiac failure should be evaluated and treated• Bevacizumab and Alemtuzumab
An oncologist’s approach to ventricular dysfunction1. 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.
MANAGEMENTOnce 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.
Background and mechanisms of QTprolongation • 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.
• 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
Nilotinibarsenic trioxide Prolongation of the QTc Interval
• 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.
• 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.
• 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
• 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.
• Skin Toxicity Of Epidermal growth factor receptor (EGFR) inhibitors.• Skin Toxicity Of Multikinase inhibitors (sorafenib, sunitinib,imatinib)
• Skin Toxicity Of Epidermal growth factor receptor (EGFR) inhibitors.• Skin Toxicity Of Multikinase inhibitors (sorafenib, sunitinib,imatinib)
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.
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)
• 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)
• 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 .
• 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.
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.
• 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
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)
Hair changes• Very characteristicare the long, curly, rigid eyelashes, termedTrichomegaly• The eyebrows become thicker and more rigid as well, with lateral thinning.• Slow growth of scalp hair,and beard.
Other skin toxicities• Telangiectasia• The telangiectasia together with facialerythema, tenderness and follicular papulopustulesin the absence of comedones creates a rosacea-likepicture of the face. Unlike other telangiectasia, thelesions tend to fade over months usually leaving somehyperpigmentation• Hyperpigmentation• Mucosal changes:Conjunctivitis,.Dry mouth, apthous stomatitis.dry vulvovaginitis (especially in postmenopauzal (women) or balanitis.
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 occursin 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 sunscreendecreased severity of acneiform eruption.
Treatment of acneiform eruption• Topical metronidazole and oralminocycline 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
• 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 orpimecrolimus), 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
• Despite its efficacy for EGFR inhibitor-dependentrash, 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
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
Treatment of paronychiaAntiseptic (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) anda potent topical corticosteroid. Oral nonsteroidalanti-inflammatory drugs can be administeredto control the pain. Silver nitrate application on aweekly basis improves pyogenic granuloma
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.
Associations with outcome of therapy, predictive roleMost 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.
• Skin Toxicity Of Epidermal growth factor receptor (EGFR) inhibitors.• Skin Toxicity Of Multikinase inhibitors (sorafenib, sunitinib,imatinib)
Clinical pictureSorafenib (34%) and sunitinib (19%) may cause1-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
2- Asymptomatic subungual splinter haemorrhagesare 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.
• 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.
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
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
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.
Proteinuria:Bevacizumab 21- 41% low dose G3 22- 63% high doseVEGF 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 increasingTemsirolimus, sirolimus glomerular permeability/ injury. •Podocyte injury and focal segmental glomerulosclerosis
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
Tubular lesions1. 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
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
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 rashTtt : corticosteroids
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
• 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 .
Gastrointestinal toxicities of novel agents in cancer therapy L/O/G/O www.themegallery.com
Include:• Diarrhoea• Gastrointestinal bleeding, gastrointestinal perforation and wound- healing problems.• Hepatic toxicity.• Elevation of pancreatic enzymes
Incidence, clinical pattern and pathophysiology of diarrhoea1. 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.
Diarrhoea occurs in about 20−28% of patientsundergoing 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
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.
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)
• 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
Management of diarrhoea in patients undergoing targeted therapy1. 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 .
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
• Wound-healing complications, Gastrointestinal bleeding and gastrointestinal perforation
• 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.
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
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
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)
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 livertoxicity but imatinib is metabolised by cytochromeP450. Therefore, an increase in toxic metabolites ispossible in cases where there is use of enzymaticInducers.• Also An idiosyncratic mechanism and an immuno- allergic mechanism were probable.
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
In conclusion, little is known about the mechanismsof hepatotoxicity due to targeted agents and managementis 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.
Elevation of pancreatic enzymesElevation of lipase can be observed with the small oral multi-targeted therapies sorafenib, sunitinib and nilotinib.
Recommendations of tests according to treatment
Side effects and organ toxicity of protein kinase inhibitors observed in clinical studies.
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.”