Toxicidade De Agentes Alvo Moleculares 2006
•Download as PPT, PDF•
0 likes•1,422 views
targeted therapy toxicity
![O Grande problema da Oncologia Atual: Heterogenicidade Molecular com grande impacto no resultado de estudos fase III ,[object Object],[object Object],[object Object]](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Toxicidade De Agentes Alvo Moleculares 2006
Similar to Toxicidade De Agentes Alvo Moleculares 2006 (20)
More from Carlos Frederico Pinto
More from Carlos Frederico Pinto (20)
Toxicidade De Agentes Alvo Moleculares 2006
- 1. ICOI 2006 Toxicidade da Terapia Molecular Carlos Frederico Pinto Oncologista Clínico Hospital Regional do Vale do Paraíba e Instituto de Oncologia do Vale
- 3. Efeito Individual 0.2 0.4 0.3 0.1
- 4. O ideal Todos com o mesmo diagnóstico Terapia C Terapia B Terapia A
- 5. O real Todos com o mesmo diagnóstico Alguns respondem ao tratamento Alguns não Alguns apresentam reações adversas Por que as diferenças nas respostas?
- 6. Respeitando as diferenças Terapia padrão Respondedores não Predispostos à toxicidade Todos com o mesmo diagnóstico Terapia alternativa Sem resposta ou Com toxicidade
- 7. Farmacogenômica: Terapia padrão Respondedores não Predispostos à toxicidade Todos com o mesmo diagnóstico Terapia alternativa Sem resposta ou Com toxicidade GCCC G CC T C GCCC A CC T C
- 8. Farmacogenômica 5FU 1% da população DPD Omeprazol 2.7% EUA brancos 14.6% China 18% Japão CYP 2C19 Warfarin 3% Reino Unido CYP 2 C9 Codeina 6.8% Suécia 1% China CYP 2D6 Droga Frequencia do fenótipo de metabolismo pobre Enzima metabolizadora da droga
- 10. Intervenção Ideal Perda Terapia Empírica Terapia Dirigida Intervenção Excessiva Intervenção Insuficiente Intervenção Ótima Qualidade Perda por Excesso Perda por Terapia insuficiente
- 15. Sobrevida por Fenótipo da B-Tubulina III em câncer de pulmão tratado com taxano Months after diagnosis Cumulative survival 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 0 2 4 6 8 10 12 14 16 Dumontet, 2002 p=0.02
- 16. Terapias Moleculares e Alvos Específicos CD-52 Alemtuzumab Rituximab Imatinib Trastuzumab c-Kit bcr-abl Tersimolimus/ RAD001/ AP23573 AG-013736 Erlotinib/ Cetuximab/ lapatinib Sunitinib Sorafenib Bevacizumab TOR CD-20 EGFR PDGFR VEGFR VEGFA
- 17. Terapias atuais em CCR avançado 1 JCO 2006;24:16-24; 2 ASCO 2005; Abs 4508; 3 JCO 1999;17:2039-2043; 4 JCO 2004;22:454-463; 5 JCO 2002;20:289-296; 6 JCO 2005;23:133-141; 7 ASCO 2005; Abs 4510 40% 3%** 169* 335 Motzer et al 1,2* Escudier et al 7 Sunitinib Trial 1,2* Sorafenib TARGET (PFS 24x12m)** 11% 23% 463 255 Motzer et al 5 McDermott et al 6 Interferon-alfa Interleucina-2 Alta Dose 113 251 N Terapia Convencional 1ª Linha 3% 4% Escudier et al 3 Motzer et al 4 Citoquinas Vários (dados históricos) Terapia de 2ª Linha Convencional TKIs 2ª Linha (aprovados FDA) Taxa de Resposta (%) Referência
- 18. Tumores Malignos do Rim, Frequência e Oncogenes Lineham WM, et al. J Urol. 2003;170:2163-2172. BHD 5% Oncocitoma BHD 5% Cromofobo FH 10% Papilar tipo 2 Met 5% Papilar tipo 1 Oncogenes Frequência Relativa Tipo VHL 75% Carcinoma Células Claras
- 20. Progression-Free Survival by MSKCC Risk Status* (Independent Central Review) MSKCC Risk Factors: 0 (Favorable) MSKCC risk factors: 1-2 (Intermediate) *Motzer et al. JCO 2002;20:289-296; Excludes 17 pts from IFN- with missing data 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (Months) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Progression Free Survival Probability Sunitinib (n=143) Median not been reached IFN- (n=121) Median: 8 months (95% CI: 7 – NA) Hazard Ratio = 0.371 (95% CI: 0.214 – 0.643) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (Months) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Progression Free Survival Probability Sunitinib (n=209) Median: 11 months (95% CI: 11 – 11) IFN- (n=212) Median: 4 months (95% CI: 3 – 4) Hazard Ratio = 0.388 (95% CI: 0.281 – 0.537)
- 21. Treatment-Related Adverse Events LBA03 ASCO 2006 * Greater frequency, P <0.05 11/<1 * 51 7 51 Fatigue 0 13 5 * 53 Diarrhea 0 29 1 6 Chills <1 2 1 25 Stomatitis <1 16 <1 5 Myalgia 1 3 2 10 Ejection fraction decline <1 1 8 * 24 Hypertension 0 1 5 * 20 Hand-foot syndrome <1 8 0 1 Flu-like symptoms 0 34 1 7 Pyrexia Grade 3/4 Grade 3/4 IFN- (%) 1 33 All grade 3 44 All grade Sunitinib (%) Nausea Event
- 26. Edema periorbital associado ao imatinib
- 32. Extendendo a sobrevida em carcinoma colorretal metastático: avanços terapêuticos VEGF = vascular endothelial growth factor. Modified from Venook A. Oncologist . 2005;10:250-261. 0 3 6 9 12 15 18 21 24 Median OS (months) ? 20-21 20-21 20-21 17 16 14-15 14-15 12-13 12-13 -4-6 Bevacizumab plus FOLFOX or FOLFIRI or XELOX then unused cytotoxics Anti-VEGF with sequential combination chemotherapy Under investigation Bevacizumab plus IFL Anti-VEGF with combination chemotherapy FOLFIRI then oxaliplatin FOLFOX then irinotecan Sequential combination chemotherapy FOLFIRI FOLFOX IFL Combination chemotherapy Infusional 5-FU/LV Cape- citabine Bolus 5-FU/LV 5-FU/LV monotherapy No chemotherapy BSC Progression-free survival >50% Second-line irinotecan >50% Second-line oxaliplatin >50% Receives all 3 cytotoxics
- 35. Erbitux: acne
- 46. Ação farmacológica exagerada levando a toxicidade
- 52. O Gato de Alice Se você não sabe onde quer chegar, não importa qual caminho você vai tomar...
- 53. Carlos F. Pinto [email_address] Hospital Regional do Vale do Paraíba e Instituto de Oncologia do Vale
Editor's Notes
- BHD , Birt Hogg Dube; FH, fumarate hydratase; VHL, von Hippel-Lindau
- DDI: St. John's Wort may decrease Sutent ® plasma concentrations unpredictably; concurrent administration of Sutent ® and St. John's Wort is not recommended CYP3A4 inhibitors (e.g. ketoconazole) may increase Sutent® plasma concentrations CYP3A4 inducers (e.g. rifampin) may decrease Sutent® plasma concentrations FDI: Since it is metabolized by CYP3A4, food that contains grapefruit juice may increase Sutent® plasma concentrations
- Affects skin: skin discoloration (yellow), dryness, thickness or cracking of skin skin rash, including blisters or rash on hands and soles of feet Bone muscle pain, GI upset, weakness, hair and skin effects i.e., mouth sores
- Survival benefit is evident when bevacizumab is added to combination cytotoxic regimens. Combination regimens and sequencing increase the lines of therapy and duration of treatment. Some studies are showing that second-line combination therapy, rather than single-agent therapy, follows combination first-line treatment. Suggested Reading Venook A. Critical evaluation of current treatments in metastatic colorectal cancer. Oncologist . 2005;10:250-261.
- infection (especially cold sores or shingles) heart disease (like heart failure) an unusual or allergic reaction to sorafenib, other medicines, foods, dyes, or preservatives
- CAMPATH-1H from Cambridge Pathology development started in 80’s (Alemtuzumab) Chosen as an example that a high degree of specificity does not ensure safety particularly with a dosing regimen that does not consider pk and as an illustration of some factors influencing the pk of therapeutic proteins Single high specificity does not preclude multiple plasma concentration relationships Approved FOR THE TREATMENT OF PATIENTS WITH CLL WHO HAVE BEEN TREATED WITH ALKYLATING AGENTS AND WHO HAVE FAILED FLUDARABINE. CLL is a disease of malignant B cells rather than other leucocytes. Also used for T-cell prolymphocytic leukaemia (T-PLL) and prevention of graft versus host disease (GVHD) Clinical toxicity is characterized by first dose reaction due to cytokine release consisting of fever, rigors, rash and at time dyspnea and hypotension. The most significant toxicity is profound, prolonged lymphopenia and subsequent increased risk of opportunistic infection. Initial toxicity is controlled by initiating dosing a lower level of 3 mg daily until tolearated and increasing the dose to 10 mg daily. When this is tolearated, a 30 mg dose 3 times weekly is instituted for 12 weeks. Operates through at least 3 different mechanisms
- For the approved indication of CLL only the CD52 receptors on B lymphocytes represent therapeutic target with the expression of CD52 at the other sites representing potential sites of toxicity The approved dosing for CAMPATH includes a maintainence dosing phase of 30 mg/kg 3 times a week for a maximum of 12 total weeks inclusive of the dose escalation scheme. (3 mg to 30 mg daily with 3 to 7 days) 5% detrermined in an environment of competition between the binding of CAMPATH and other WBC’s So what’s happening to the bystander cells represented by granulocytes.
- Also not expressed on bone marrow prgenitor cells.
- Not all biologic products are intrinsically safe (like Heceptin) Pancytopenia / Aplasia: (fatal) Delayed recovery of neutrophils: 38% at two months of follow-up: 25% at 4 months Increased / new transfusion requirement during therapy ~ 68% Prolonged CD4+ recovery: 27% < 200/ul at 4 months Autoimmune – thrombocytopenia
- Main task issues – to identify target organs and toxicities; find a safe starting dose, dose escalation scheme and dosing regimen
- Environmental issues
- Knowing the right questions; infection leading to TB or increase propensity to have the flu Animals predictive of TPO MDGF IL12