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PREDICTORS AND GRADING OF CHEMOTHERAPY TOXICITY

PREDICTORS AND GRADING OF CHEMOTHERAPY TOXICITY . Dr. Hülya BAYIZ Atatürk Chest Diseases and Thoracic Surgery Research & Training Hospital , Ankara. Cytotoxic treatment i s the art of differential poisoning: killing the cancer without killing the patient.

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PREDICTORS AND GRADING OF CHEMOTHERAPY TOXICITY

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  1. PREDICTORS AND GRADING OF CHEMOTHERAPY TOXICITY Dr. Hülya BAYIZ Atatürk ChestDiseasesandThoracicSurgeryResearch & TrainingHospital, Ankara

  2. Cytotoxic treatment is the art of differential poisoning: killing the cancer without killing the patient

  3. Common side effects of chemotherapy • Myelosupression • Allopecia • Mucositis • Nausea – vomiting • Tiredness • Reduced fertility

  4. Treatment related factors Chemotherapy scheme Relative dose intensity Chemotherapy line Chemotherapy toxicity • Patient related factors • Age • Gender • Poor performance status • Poor nutritional status • Comorbidity • Polypharmacy • Tumour related factor • Advanced stage disease • High tumour burden

  5. Myelosuppressive chemo regimen Hx of severe and/or febrile neutropenia Extensive prior chemotherapy Previous / concurrent radiation Neutropenia • Advanced or uncontrolled disease • Bone marrow involvement • Poor nutrition • Poor performance status • Age • Elevated LDH • Immune function (comorbidity) Example NSCLC Paklitaxel / cisplatin Docetaxel / carboplatin SCLC Etoposide / cisplatin Topotecan +/- paclitaxel Clin Oncol Nurs 2008;2: 29;38

  6. Myelosuppressive chemo regimen Nutritional deficiency / malabsorption Previous radiation tomorrow Anemia • Blood loss – surgical, GI, GYN • Transfusion within post 6 months • Chronic illness • Renal insufficiency • Pre-existing anemia Cisplatin / 5-FU Cyclophosphamide / doxorubion Paclitaxel cisplatin veya carboplatin Etoposid cisplatin Topotecon Clin Oncol Nurs 2008;2: 29;38

  7. Nausea/Vomiting • Emetogenic treatment regimen • Female • < 50 years • Radiation to abdomen • Hx of hyperemesis with pregnancy • GI malign and/or adv/large tumour burden • Prior inadequate control of emesis • Motion sickness High emetogenic chemotheuropatics (30%- 90%) Busulfan > 4 mg/gün Carboplatin Cyclophospamide Epirubicin Lomustine Cytarabine Daunorubicin Methotraxate > 1000 mg/m2 Idarubicin Ifosfamide Dacorbazine Streptozocin Very high (99%) cisplatin Clin Oncol Nurs 2008;2: 29;38

  8. Oral mucositis • Chemotherapy regimen • Current or prior radiation to H&N area • Hx of mucositis • Hx or presence of dental disease •  Salivation • Geriatric patient • Poor fitting oral protez Docetaxel Vinblastin Metothrexate Etoposide Floxuridine Thioguanine 5 FU Bleomycin Cytarabine Clin Oncol Nurs 2008;2: 29;38

  9. Constipation Diarrhea • Chemotherapy regimen • Hx of constipation • Antiemetics • Inactivity • Geriatric patient • Current narcotic use • Oral iron • Chemotherapy regimen • Abd/pelvic radiotherapy • Hx of diarrhea / bowel disease • Enteral feeding • Lactose intolerance Thalidomide Vinblastine Vincristine Vineralbine 5-FU Irinotecan Docetaxel Oxalipotin Erlotinib Gefitinib Clin Oncol Nurs 2008;2: 29;38

  10. Drug specific side effects • Nephrotoxicity  Cisplatin, ifosfamid, mitomycin, methotrexate • Peripheral Neuropathy Cisplatin, carboplatin, Docetaxel, paclitaxel, vincristine, vinorelbine, vinblastine • Pulmonary toxicity  Bleomycin • Cardiac Toxicity  Doxorubicin, Epirubicin, liposomal doxorubicin, mitoxantrone, troztuzunol Clin Oncol Nurs 2008;2: 29;38

  11. Age Related Physiologic Changes and Susceptibility to Chemotherapy Related Toxicity J Supp Oncol 2003;118-24 Eur J Cancer 2007;43:2235-41

  12. Factors Influencing G4 Hematologic Toxicity >70 years old J Clin Oncol 26:2008 (Abst 9505

  13. Gender effect on chemotherapy toxicity in SCLC J Clin Oncol 2005 ; 23; 850-56

  14. The effect of pretreatment factors on chemotherapy toxicity in advanced NSCLC: Univariate analysis J Thorac Oncol 2006;1:556-63

  15. The effect of pretreatment factors on chemotherapy toxicity in advanced NSCLC: Multivariate analysis Hgb, hemoglobin, WBC, white blood cells; PLT, platelets; aRegardless of relationship to study therapy. bAt least possibly related to study therapy. J Thorac Oncol 2006;1:556-63

  16. Severe adverse event probability = Non-hematologic = g (x) = (-1.93) + (0 if male) Or (0.54 if female) + (0.02 x age in years) + (0 if PS =0) or (0.36 if PS =1) Or (0.83 if PS = 2 or 3) Hematologic = g (x) = (-0.41) + (-0.11 x WBC value in 109 /L) + (-0.05 x Hgb value in g/dL) + (-0.09 x Plt value in 109 /L) + (0.04 x age in years) + (0 if male) or (0.47 if female) J Thorac Oncol 2006;1:556-63

  17. Doselimitingtoxicitypredictors in targetedtherapy: multivariateanalysis Odds Ratio 95% CI P Predictors of all SAEs     ECOG performance status 1.91 1.36 to 2.69 <.001     Age/10-year increase 0.90 0.78 to 1.05 .181     Charlson score 1.18 0.94 to 1.49 .158     Prior radiotherapy 0.79 0.56 to 1.11 .176     No. of target lesions 1.06 0.98 to 1.14 .161     log (LDH ULN) 1.39 1.03 to 1.88 .030     Albumin ULN 0.13 0.02 to 0.93 .043 Predictors of attributable SAEs     ECOG performance status 1.37 1.01 to 1.88 .046     Body-surface area 0.27 0.10 to 0.70 .007     Charlson score 1.20 0.98 to 1.48 .079     Prior radiotherapy 0.72 0.46 to 1.14 .164     log (LDH ULN) 1.23 0.93 to 1.63 .152     Creatinine ULN 2.91 1.14 to 7.44 .026     No. of prior systemic chemotherapy regimens 1.21 0.91 to 1.60 .184 Pond, G. R. et al. J Clin Oncol; 26:1324-1330 2008

  18. (A) Nomogram for predicting any serious adverse event during cycle 1. (B) Nomogram for predicting any attributable serious adverse event during cycle. Abbreviations: ULN, upper limit of normal; LDH, lactate dehydrogenase; RT, radiation therapy; BSA, body-surface area. Pond, G. R. et al. J Clin Oncol; 26:1324-1330 2008

  19. The same dosage Minimal Severe Life threatening toxicity • Polymorphism in protein affecting drug disposition • Polymorphism in drug metabolizing enzymes

  20. Pharmacogenomics • The prediction of drug toxicity based on a patient’s genetic profile, • preferably assayed using a widely available and inexpensive genetic test • performed on an easily obtainable biological sample, such as peripheral blood.

  21. Genetic Polimorphisms Related To Chemotherapy Toxicity J Supp Oncol 2007;5;9-14

  22. Thiopurine Methyltransferase (TPMT) Genotype Effect on Mercaptopurine (6-MP) Therapy J Supp Oncol 2007;5;9-14

  23. UGT1A1 Genotype Effect on Irinotecan Therapy J Supp Oncol 2007;5;9-14

  24. ERCC1 C8092A Polymorphism and G3-4 Cisplatin Toxicity Cancer Sci, 2008

  25. Prediction scores of docetaxel-induced leukopenia/neutropenia using ABCC2 RS12762549 and SLCO183 rs 1045585 7.00 [2.95-16.95]0.0000057 Cancer Sci 2008;5:967-72

  26. INTERNATIONAL TOXICITY GRADING SYSTEMS • NCI (National Cancer Institute) • CTCAE (Common Terminology Criterria for Adverse Events) version 3.0 • CTC (Common Toxicity Criterria) version 2.0 • CTC (Common Toxicity Criterria) version 1.0 • WHO (World Health Organization) • SWOG (South Western Oncology Group) • Other

  27. Variables Related to Toxicity Assessment and Reporting J Clin Oncol 2002; 20:52-57

  28. Toxicity Reporting in Head and Neck Chemoradiotherapy Trials J Clin Oncol 2004; 22:1, 19-22

  29. CTCAE Organization • Adverse events integrated into document without distinguishing between acute, late, chronic or permanent • Adverse event that maybe or may not be considered related or caused by medical treatment or procuder integrated into document • Adverse event categorization is based on pathophysiological and anatomical • Adverse event – any unfavorable symptom, sign or disease (including abnormal laboratory finding) • Each adverse event is assigned a code, short name, remark and also considered one the other features

  30. Musculo Skeletal / Soft Tissue

  31. ADVERSE EVENT

  32. ADVERSE EVENT ATTRIBUTION

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