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Gabriela Sousa IPO Coimbra Espinho 2011

CARCINOMA DE CÉLULAS RENAIS Como tratar as toxicidades da terapêutica sistémica?. Gabriela Sousa IPO Coimbra Espinho 2011. Guidelines…. These biologic agentes present a toxicity profile very different from that “convencional” chemotherapeutic agents. Targeted Therapy and Toxicity:.

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Gabriela Sousa IPO Coimbra Espinho 2011

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  1. CARCINOMA DE CÉLULAS RENAIS Como tratar as toxicidades da terapêutica sistémica? Gabriela Sousa IPO Coimbra Espinho 2011

  2. Guidelines… These biologic agentes present a toxicity profile very different from that “convencional” chemotherapeutic agents

  3. Targeted Therapy and Toxicity: Their use requires a knowledge of possible side-effects… Gore M, British Journal of Cancer (2011) 104(3), 399 –406

  4. Targeted Therapy and Toxicity: • General Toxicity • Cardiovascular and respiratory • Gastrointestinal, hepatic, renal • Endocrinologic and laboratory • Bone marrow toxicity • Skin and mucosal toxicity FATIGUE INFECCIONS HYPERTENSION CARDIAC EVENTS BLEEDING THROMBOEMBOLISM DYSPNOEA PNEUMONITIS ANOREXIA NAUSEA VOMITING DIARRHOEA PROTEINURIA HYPERCREATININ HYPERBILIRUBIN  ALT AND  AST HYPOTHYROIDISM HYPERGLYCAEMIA HYPERCHOLESTERO HYPERTRIGLYCERID HYPOPHOSPHATEM HYPERLIPASEMIA HYPERAMYLASEMIA NEUTROPENIA LYMPHOPENIA ANAEMIA THOMBOCYTOPENIA MUCOSITIS HAND-FOOT SYND RASH

  5. GENERAL TOXICITY: - FATIGUE - INFECTIONS

  6. FATIGUE Defined asa distressing, persistent and subjective sense of tiredness that affects 70-100% of patients with cancer Moderate fatigue (grade 2) reflectsa reduction in performance status by 1 ECOG level or 20% in Karnofsky PS Larkin JM et al. Oncologist. 2010; 15: 1135-46

  7. FATIGUE 1. Motzer et al. J Clin Oncol 2009; 27: 3584-3590. 2. Escudier et al. N Engl J Med 2007; 356: 125-34. 3. Sternberg et al.J Clin Oncol 2010; 28: 1061-1068. 4. Escudier et al. Lancet 2007; 370: 2103-11

  8. FATIGUE SLEEP DISTURBANCE PAIN STOMATITIS DYSGEUSIA DIARRHOEA COMORBIDITIES EMOTIONAL DISTRESS ANAEMIA HYPOTHYROIDISM NCCN Practice Guidelines in Oncology: Cancer-Related Fatigue v.1. 2007 NCCN Practice Guidelines in Oncology: Cancer-Related Fatigue v.1. 2011

  9. FATIGUERecommended Interventions • General strategies • - Self-monitoring (e.g. diary) • - Energy conservation • Non-pharmacological • - Support groups • - Exercise, massage therapy • Pharmacological • - Treat co-morbidities (anaemia) • - Consider sleep medication • - Consider psychostimulants NCCN Practice Guidelines in Oncology: Cancer-Related Fatigue v.1. 2011

  10. FATIGUE • Grade Grade 0: No symptoms Grade 1: Mild Grade 2: Moderate or causing difficulty with activities of daily life Grade 3: Severe, interfering with activities of daily life Grade 4: Disabling Consider dose reduction or treatment suspension NCI CTCAE v3 Di Lorenzo et al. Eur Urol 2011; 59: 526-540.

  11. INFECTIONS mTOR Inhibitors important immunosuppression • Pneumonia • Aspergillosis • Candidiasis • Reactivation of hepatitis B virus • Hudes G et al. New Engl J Med 2007; 356: 2271-81 • Motzer et al. Lancet 2008; 372: 449-56

  12. INFECTIONSRecommended Interventions • Patient and family should receive counselling to prevent infections (wash hands) • Signs or symptoms possibly indicating an infection before or during treatment should be investigated promptly Antibody titres (Ac HBV, HCV) Se HBV+ prophylatic antiviral treatment (lamivudine, 300 mg/d) 1-2wk BEFORE start mTOR inhibitors Di Lorenzo et al. Eur Urol 2011; 59: 526-540.

  13. CARDIOVASCULAR AND RESPIRATORY TOXICITY

  14. ARTERIAL HYPERTENSION

  15. HYPERTENSION – Screening Take a complete medical history Performed a physical examination Assess BP and Cardiovascular Risk • BP ≥ 180 mmHg systolic and/or ≥ 110 mmHg diastolic • High Systolic BP (>160 mmHg) with low diastolic BP (<70 mmHg) • Diabetes mellitus • Metabolic syndrome • Three cardiovascular risk factors • Established cardiovascular or renal disease • Subclinical organ damages (left ventricular hypertrophy, ↓ clearance creatinina, microalbuminuria or proteinuria) 2007 Guidelines for the management of Arterial Hypertension of ESH and ESC

  16. HYPERTENSION – Management BP ≥ 140/90 mmHg: start anti-hypertensive terapy Cardiovascular Risk: high or very high, recommended a cardiologist consultation BP < 160/100 mmHg: start or continue anti-cancer therapy Monitor BP at least every week Add anti-hypertensive drug to obtain a BP<140/90 mmHg 2007 Guidelines for the management of Arterial Hypertension of ESH and ESC

  17. HYPERTENSION – Management Definition (NCI-CTC 3.0) Management Grade 1: Asymptomatic, transient (<24 h) increase: >20 mmHg diastolic or > 150/100 if BP normal Grade 2: Recurrent or persistent (>24 h) or symptomatic increase: >20 mmHg diastolic or 150/100 Grade 3: requiring more than one drug or more intensive treatment than previously Grade 4: Life-threatening consequences (hypertensive crisis) • No intervention indicated 14.7% Consider anti-hypertensive treatment Dose reduction if treatment ineffective Dose discontinuation if hypertension becomes severe or uncontrolled Carefully evaluate to re-start treatment after 1st event, STOP after 2nd event 5.4%

  18. HYPERTENSION - Management ANTIHYPERTENSIVE AGENTS Selected according to the individual patient´s comorbidities, drug interactions, and contraindications Thiazides (hydrochlorothiazide 12.5 -100 mg) Anti-aldosterone diuretics (spironolactone 100-400 mg) Beta-blockers (atenolol 50-100 mg) ACE inhibitors (lisinopril 5-40 mg) Angiotensin II receptor blockers (losartan 50-100 mg) Positive effects in patients with heart failure Dihydropyridine calcium antagonists (amlodipina 5-10 mg/d) Benefit patients with angina pectoris

  19. CARDIAC TOXICITY • TKI – associated cardiotoxicity was reported in approximately 10% of patients • Cardiac damage related to TKI may occur more frequently that reported to clinical trials … • Datailed cardiovascular monitoring during treatment reveal early signs of myocardial damage Schmidinger M, et al. J Clin Oncol 2008;26: 5204-12

  20. CARDIAC TOXICITY • Reduction of LVEF • Conduction disturbances • ST-segment or T-wave changes (early signs?) • Elevated cardiac serum markers (TNT, CK-MB, BNP, pro-BNP) • Significant clinical symptoms (angina, dyspnoea, dizziness) • Myocardial infarction BNP=B-natriuretic peptide CK-MB=creatinine kinase MB mass TNT=troponin T Schmidinger M, et al. J Clin Oncol 2008;26: 5204-12

  21. CARDIAC TOXICITYMonitoring-Recommendations • Before treatment: • history of coronary artery disease • Electrocardiogram (ECG) – QT interval • Echocardiography – LVEF • Cardiac serum markers, including CK, CK-MB, TNT, BNP and pro-BNP • During treatment: • repeat ECG and serum markers monthly • echocardiography every 2–3 months BNP=B-natriuretic peptide CK=creatinine kinase CK-MB=creatinine kinase MB mass TNT=troponin T Schmidinger M, et al. J Clin Oncol 2008;26: 5204-12

  22. CARDIAC TOXICITYMonitoring-Recommendations • Monitor LVEF: • High-risk: baseline, every cycle x 4, then every 2-3 cycles • Low-risk: baseline and every 3 cycles • Monitor QT interval, electrolytes: • Caution with pre-existing QT prolongation or receiving anti-arrhythmics • Avoid other agents that prolong the QT interval • Maintain normal serum Mg2+ and K+ DI Lorenzo G, et al. Eur Urol 2011;59: 526-40

  23. CARDIAC TOXICITYMonitoring-Recommendations • TREATMENT SUSPENSION: • Cardiac symptoms • LVEF decrease to <50% or ≥ 20% below baseline DI Lorenzo G, et al. Eur Urol 2011;59: 526-40

  24. BLEEDING / THROMBOEMBOLISM Anti-VEGF Agents alter the haemostatic balance Bevacizumab -  risk of arterial and venous thromboembolism,  bleeding events Sorafenib Sunitinib • risk arterial thromboembolism • bleeding events Incidence of 7% fatal intracerebral haemorrhage (4 of 5 patients with brain metastasis)

  25. BLEEDING / THROMBOEMBOLISMRecommended Interventions • Medical History • Frequent clinical examinations • Immediate investigation of any suspicious symptoms Grade 2- 4 thrombotic or bleeding events Require treatment suspension and appropriate therapy until recovery to grade 1 Di Lorenzo et al. Eur Urol 2011; 59: 526-540.

  26. DYSPNOEA / PNEUMONITIS • Many mechanisms have been proposed, including: • Cell-mediated auto-immunity and T-cell-mediated delayed-type hypersensitivity • The exact molecular basis remains unknown 1. Hudes G et al. New Engl J Med 2007; 356: 2271-812. Motzer et al. Lancet 2008; 372: 449-56

  27. DYSPNOEA / PNEUMONITIS Recommended Interventions • Patients should be warned to promptly report symptoms such as dyspnoea or cough Spirometry Torax Radiography CT Scan

  28. NON-INFECTIOUS PNEUMONITIS • Ground glass-opacity • Parenchymal consolidations • Pleural effusion

  29. NON-INFECTIOUS PNEUMONITIS Clinical Management Definition (NCI-CTC 3.0) Management Grade 1: Asymptomatic, radiographic findings only Grade 2: Symptomatic not interfering with ADL Grade 3: Symptomatic, interfering with ADL, oxygen indicated Grade 4: Life-threatening: ventilation support indicated • No intervention indicated • Depending on severity of symptoms: • Consider dose interruption or reduction • Consider corticosteroids • Interrupt treatment • Corticosteroids if infectious cause is excluded • Hold treatment until recovery to grade 1 • Discontinue permanently treatment 14.7% 5.4%

  30. GASTROINTESTINAL HEPATIC AND RENAL TOXICITY

  31. GASTROINTESTINAL TOXICITY 1. Motzer, et al, ASCO 2007; 2. Escudier, et al. NEJM 20073. Escudier, et al. Lancet 2007; 4. Hudes, et al. NEJM 2007; 5.Bhojani, et al. Eur Urol 2007

  32. GASTROINTESTINAL TOXICITY SYMPTOMATIC MEDICATIONS Nausea and/or vomiting Metoclopramide (10-20 mg/d) Ondansetron (8-32 mg/d) Anorexia Megestrol acetate (160 mg/d)

  33. DIARRHOEA *NCI CTCAE v3

  34. DIARRHOEA - Management • Treatment should start at very first signs: • advise patient to take loperamide 2 mg regularly • At occurrence: • loperamide: 4 mg, rather than 2 mg after each unformed stool, max. 12 mg/day • avoid spicy food, lactose containing fluids, fruits except grated apples (pectin) • follow diet (bananas, rice, potatoes)

  35. HEPATIC TOXICITY - About half patients exposed to sunitinib or pazopanib showed elevated transaminases and ¼ showed  bilirubin levels • Antioxidant substances: • N-acetylcysteine (600 mg/d) • Glutathione (600-1200 mg/d) Di Lorenzo et al. Eur Urol 2011; 59: 526-540.

  36. Recommended liver monitoring and management with pazopanib1 Prior to Pazopanib Treatment Monitor serum liver tests Every 4 weeks for 4 months minimum During Treatment Isolated ALT ≤8X ULN ALT >3X ULN ANDTBL >2X ULN ALT >8X ULN Interrupt until ALT Grade 1 or baseline Continue treatment Direct / total bilirubin >35% Reintroduce, if warranted, at lower dose YES NO Weekly tests until ALT Grade 1 or baseline Discontinue if ALT >3X ULN recur Discontinue Continue • Votrient Summary of Product Characteristics, 2010.

  37. RENAL TOXICITY

  38. MUCOSAL AND SKIN TOXICITY

  39. Characteristics dysgeusia, dysphagia, sensitivity and sores (including cheilitis) oral changes (‘functional mucositis’) do not have the appearance and severity of chemotherapy-induced mucositis MUCOSAL TOXICITY Creel T, et al. ISNCC 2006; Wood LS. Community Oncology 2006;3:558–562

  40. MUCOSITIS • Grade • Grade 0: No symptoms • Grade 1: Sore mouth, no ulcers • Grade 2: Sore mouth with ulcers, but able to eat normally • Grade 3: Liquid diet only • Grade 4: Unable to eat or drink NCI CTCAE v3

  41. BEFORE TREATMENT - Treatment of caries and dental disease - Education regarding the importance of orodental hygiene and to develop a daily routine of oral care DURING TREATMENT - Clean teeth after meals and before sleep - Avoid painful stimuli (hot food and drinks, spicy food, alcohol and smoking) - Regular inspection of mouth - Provide comfort measures (lubrication of the lips, topical anaesthesia and analgesics) - Prompt treatment of mucositis symptoms and oral infections MUCOSITIS Management

  42. Oral care protocols (dental work to eliminate caries) Mouthwashes with mixed actions (benzydamine hydrochloride) Topical anaesthetics (viscous lignocaine and xylocaine) Antiseptics (chlorhexidine) Antifungal agents (nistatina) Mucosal barriers and coating agents (sucralfate) MUCOSITIS Management

  43. HAND–FOOT SYNDROME • Symptoms affect hands and feet • Predominantly on pressure points • Distinct from HFS observed with chemotherapy (capecitabine, liposomal doxorubicin) • Impairment of keratinocyte cell interaction 1Gore ME, et al. J Clin Oncol 2007;25(18S):Abstract 5010; 2Robert C, et al. Lancet Oncol 2005;6(7):491–500; 3Webster-Gandy JD, et al. Eur J Oncol Nurs 2007;11(3):238–246

  44. HAND–FOOT SYNDROMEClinical Course • Occurs in the first 6 weeks, often weeks 1–2 • Should be treated immediately • Grade 1–2 may resolve with symptomatic treatment, allowing full dose maintenance • Completely reversible at treatment discontinuation

  45. HAND–FOOT SYNDROME

  46. HAND–FOOT SYNDROME Grade 2 Grade 3

  47. HAND–FOOT SYNDROMERecommendations • Initialnonpharmacologic measures • patients’ recommendations: • Manicure and pedicure before and during treatment • Use appropriate tools to aid in callus removal • Use shock absorbers for pressure points, sandals, cotton gloves and/or socks • Wear well-padded but nonconstrictive footwear • Avoid warm and/or hot water or objects • Tight-fitting shoes • Apply an alcohol-free moisturizer

  48. HAND–FOOT SYNDROMERecommendations • Pharmacologic interventions • Corticosteroids have no proven efficacy • Fatty ointment containing lecithin, aloe vera, D-panthenol and urea • Delay and adjust treatment if grade 3 -4 toxicity occurs

  49. RASH BSA=body surface area 1Gore ME, et al. J Clin Oncol 2007;25(18S):Abstract 5010

  50. RASH - Grade 2 • Prominent on trunk • Small erythema • Tendency for confluence

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