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Oxaliplatin induced hypersensitivity reaction Oxaliplatin induced hypersensitivity reaction Presentation Transcript

  • 2013. 12. 25 臨床藥學與藥物科技研究所 研究生 : 陳秋縈 指導老師 : 林妏娟藥師、葉裕民醫師 ADR report
  • 成大藥物不良反應通報表 病患基本資料 床號:11B*** 病歷號:******** 姓名: ○○○ 性別:男 報告者:陳秋縈 電話:5693 科部:成大臨床藥學與藥物科技研究所 出生年月日(或年齡): 1979/05/06 (34歲) 報告日期: 2013/12/25 請簡述該不良反應:Hypersensitivity reaction 懷疑引起該不良反應之藥品 處方日期 反應發生日期 停藥日期 Oxaliplatin 2013/02/01 2013/04/04 2013/04/19 2013/05/06 2013/05/06 該不良反應於何處發現?  護理紀錄  病歷  訪視病人 其他:ADR通報系統 若已知該不良反應所造成的結果或處置,請簡述: 停止滴注oxaliplatin,並給予Hydrocortisone 100mg、Epinephrine 0.5mg及 Diphenhydramine 30mg治療,病人的過敏反應有緩解。 2
  • 成大藥物不良反應通報表 II. 不良反應有關資料 11. 不良反應結果  A. 死亡,日期︰ 年 月 日,死亡原因︰  B. 危及生命  C. 導致病人住院  D. 造成永久性殘疾  E. 延長病人住院時間  F. 需作處置以防永久性傷害  G. 先天性畸形  H. 非嚴重不良反應(請敘述) 1. 發生日期︰2013/04/04 2. 通報者獲知日期︰2013/04/04 4. 通報者資料 姓名︰陳秋縈 電話︰5693 屬性: 藥師 服務機構︰成大醫院 地址:台南市北區勝利路138號 職稱︰ 藥師 I. 病人基本資料 5.識別代號︰ (供通報者辨識用) 6. 性別︰ 男  女 7. 年齡︰34歲 8. 體重︰62.2 公斤 9. 身高︰168.5 公分 3
  • 其他相關資料 Past Medical History • Rectal cancer, adenocarcinoma, KRAS mutation: G12D, with multiple liver metastasis and possible R’t cardiac involvement, stage IV, s/p FOLFIRI + Bevacizumab*3, in progression, s/p FOLFOX*4 • Alcoholic hepatitis Drug Allergy Family History • NKDA • Not contribution Social History • Smoking (+) • Betel nut (+) • Drinking (+) • Drug abuse (-) 4
  • 通報事件之描述 (1) NCKUH GI OPD • Lower abdominal cramping pain and bloody stool for month Colonscopy • Rectal tumor mass at 10 cm above AV (anal verge) • External hemorrhoid Biopsy and pathologic finding • Adenocarcinoma Abdominal CT • Rectal tumor with pre-sacral invasion • Multiple liver metastasis and one nodular lesion at right cardiac ventricle  T4N2M1 stage IV 分子診斷檢驗報告: KRAS mutation: G12D 2012 11/20 11/05 10/26 10/01 5
  • 通報事件之描述 (2) 6 10/26 Diagnosis Rectal cancer with liver metastasis, T4N2M1 stage IV 11/29 2012 01/14 2012/11/1 12/14 2013/1/4 1/21 CEA.(ng/mL) 1739 2752 3373 3042 FOLFIRI + Bevacizumab (3 cylcles) Premedication Diphenhydramine, Dexamethasone, Metoclopramide, Granisetron, Atropine C/T drug Irinotecan, Leucovorin, 5FU, Bevacizumab CEA  abd CT: increased size of liver and cardiac metastasis 02/01 05/06 mFOLFOX6 (7 cylcles) Premedication Diphenhydramine, Dexamethasone, Metoclopramide, Granisetron, C/T drug Oxaliptin Leucovorin 5FU 2013 765 ADR
  • 通報事件之描述 - 1st hypersensitivity 7 4/4 - 5th mFOLFOX6 • 168.5cm, 62.2kg, BSA: 1.71 • TPR: 36/85/19, BP: 116/86 ADR EVENT 15:10 Oxaliplatin (85mg/m2) 150mg in D5W 250ml IVD 2hr 15:44 (已滴注Oxaliplatin 38.4mg) Dyspnea, erythema and generalized itching, 焦躁坐立不安, 流鼻水 TPR: 36.6/96/30, BP: 128/72, SpO2: 96% MANAGEMENT 15:45 Hold oxaliplatin Hydrocortisone 100mg IVD stat 15:46 Epinephrine 0.5mg IM stat 15:50 Diphenhydramine 30mg IVD stat 16:10 皮膚泛紅、流鼻水、呼吸喘情形皆有改善 TPR: 36.6/104/21, BP: 129/74, SpO2: 98% 4/5 5‐FU and leucovorin via infusor
  • 通報事件之描述 – 2nd hypersensitivity 8 4/19 - 6th mFOLFOX6 • 168.5cm, 63.1kg, BSA: 1.72 • TPR: 36.2/92/18, BP: 126/82 • Add ranitidine and prolong oxaliplatin infusion time ADR EVENT 16:10 Ranitidine 50 mg IVD 17:15 Oxaliplatin (85mg/m2) 150mg in D5W 250ml IVD 6hr 18:00 (已滴注Oxaliplatin 19.2mg) 全身癢,前胸臉頰皆有紅疹情形,煩躁不安 TPR: 37.6/106/20, BP: 136/89 MANAGEMENT 18:00 Hold oxaliplatin 18:02 Epinephrine 0.3mg IM stat Diphenhydramine 30mg IVD stat 18:09 Hydrocortisone 100mg IVD stat 20:00 主訴已無不適情形,TPR: 36.6/88/18, BP: 113/86 21:15 5‐FU and leucovorin via infusor
  • 通報事件之描述 – 3rd hypersensitivity 9 5/06 - 7th mFOLFOX6 • Discussion with patient and patient want to receive desensitization therapy • 5/03 5-FU and Leucovorin, 5/06 oxaliplatin desensitization protocol ADR EVENT 11:58 Ranitidine 50 mg IVD 12:40 Oxaliplatin 0.014mg in D5W 100ml IVD 1hr [bag 1] 13:55 Oxaliplatin 0.14mg in D5W 100ml IVD 1hr [bag 2] 15:00 Oxaliplatin 1.4mg in D5W 100ml IVD 1hr [bag 3] 16:55 Oxaliplatin 14mg in D5W 100ml IVD 1hr [bag 4] 17:30 (已滴注bag4 35 ml, oxaliplatin total dose: 50.6mg) 全身發紅起紅疹,雙手、雙腳及後背癢,大腿內側尤其明顯 TPR: 36/87/18, BP: 121/89 MANAGEMENT Hold oxaliplatin, 給予冰敷 Hydrocortisone 100mg IVD stat Diphenhydramine 30mg IVD stat &q12h 18:00 過敏情形改善,全身之紅疹幾乎皆以消退,無皮膚癢之主訴 Antiemetics (IVD before C/T) Diphenhydramine 30 mg QD IVD Dexamethasone 20 mg QD IVD Metoclopramide 10 mg Q8H IVD Granisetron 3 mg QD IVD Ranitidine 50 mg QD IVD (before oxaliplatin) Hydrocortisone 100 mg QD IVD 4hr (oxaliplatin bag5 30min前給) C/T drug Conc (mg/ml) Oxaliplatin 0.014 mg in D5W 100ml IVD 1hr [bag 1] 0.00014 Oxaliplatin 0.14 mg in D5W 100ml IVD 1hr [bag 2] 0.0014 Oxaliplatin 1.4 mg in D5W 100ml IVD 1hr [bag 3] 0.014 Oxaliplatin 14 mg in D5W 100ml IVD 1hr [bag 4] 0.14 Oxaliplatin 126 mg in D5W 100ml IVD 4hr [bag 5] 1.26 Oxaliplatin desensitization protocol
  • Drug profile 10 1st 2nd 3rd 4th 5th 6th 7th 2/1 2/15 3/2 3/22 4/4 4/19 5/3 5/6 Antiemetics (IVD before C/T) Diphenhydramine 30 mg D1 Dexamethasone 10mg D1 20 mg Metoclopramide 10mg q8h D1,2 Granisetron 3mg D1 Ranitidine 50mg D1 Before oxaliplatin Hydrocortisone 100mg Before bag 5 C/T drug Oxaliplatin (85mg/m2 ) in D5W 250ml IVD 2hr 150 mg IVD 6hr Desensitization Leucovorin (400mg/m2 ) in D5W 250ml IVD 2hr 700 mg 680 mg 5-FU (2400mg/m2 ) in D5W 500ml IVD 46hr pump 4200 mg 4150 mg 4100 mg Long-term medication MgO 250mg tid Bisacodyl 10mg hs Morphine 5mg q4h Naproxen 250mg bid Estazolam 2mg hs Chlorpromazine 50mg prn ADR ADR ADR
  • 相關檢查及檢驗數據 11 2/4 2/6 2/15 2/23 3/12 4/3 4/13 4/30 5/13 CREA(mg/dL) 0.7 0.68 0.71 0.72 0.7 0.73 0.8 0.86 0.81 eGFR ≧90 ≧90 ≧90 ≧90 ≧90 ≧90 ≧90 ≧90 ≧90 AST(U/L) 44 31 28 38 47 46 55 73 ALT(U/L) 21 37 22 32 27 30 24 32 33 NA(mmol/L) 139 144 K(mmol/L) 3.6 3.8 WBC(10^3 /μL) 17.1 19.6 13.8 12.6 16 12.8 10.3 12.1 14.7 Seg(%) 75 87 76.3 66.6 72.5 69.3 70.8 65.1 69.2 Eos(%) 1 0 0.3 0.2 0.2 0.3 0.6 1.6 1.3 Baso(%) 0 0 1.2 0.3 0.4 0.3 0.4 0.7 0.5 Mono(%) 5 2 7.4 8 10.1 8.6 8.4 9.8 10.6 Lymph(%) 16 10.5 14.8 24.9 16.8 21.5 19.8 22.8 18.4 RBC(10^6 /μL) 4.66 4.26 4.28 4.29 4.32 4.31 4.11 4.25 Hb(g/dL) 15 14.9 13.5 13.5 13.7 13.5 13.6 13.1 13.1 RDW(%) 14.7 15 14.7 14.6 14.4 14.8 14.7 14.9 Plt(10^3 /μL) 254 297 374 343 297 252 277 308 327 FOLFOX 5 6 71 2 3 4 ADR 2/1 2/15 3/2 3/22 4/4 4/19 5/6
  • Outline Oxaliplatin induced hypersensitivity reaction  Incidence and clinical features  Pathophysiology  Management ADR evaluation Case discussion Take home message  Patient evaluation  Treatment strategies
  • Outline Oxaliplatin induced hypersensitivity reaction  Incidence and clinical features  Pathophysiology  Management ADR evaluation Case discussion Take home message  Patient evaluation  Treatment strategies
  • 14 Hypersensitivity Reaction (HSR) Anticancer Drugs. 2009 Jan;20(1):1-6. Met Based Drugs. 2010;2010. pii: 207084. Type Mediators Symptoms related I IgE Early onset symptoms: Itching, rash, angioedema, bronchospasm , anaphylactic reactions II (Cytotoxic) IgG, IgM, Hemolysis, thrombocytopenia III (Immune complex) IgG Chronic urticaria, joint pain, proteinuria IV (Delayed, cell-mediated) T-cells Delayed reactions, hours or days after infusion: Contact dermatitis, morbilliform eruptions Definition • Unexpected reactions with signs and symptoms inconsistent with known toxicity of the drugs (unpredictable, not related to the pharmacologic reactions) Symptoms 1st HSR Dyspnea, erythema and generalized itching, 焦躁坐立不安, 流鼻水 2nd HSR 全身癢,前胸臉頰皆有紅疹情形,煩躁不安 3rd HSR 全身發紅起紅疹,雙手、雙腳及後背癢,大腿內側尤其明顯 
  • Which is the culprit drug ? 15 1st 2nd 3rd 4th 5th 6th 7th 2/1 2/15 3/2 3/22 4/4 4/19 5/3 5/6 Antiemetics (IVD before C/T) Diphenhydramine 30 mg D1 Dexamethasone 10mg D1 20 mg Metoclopramide 10mg q8h D1,2 Granisetron 3mg D1 Ranitidine 50mg D1 Before oxaliplatin Hydrocortisone 100mg Before bag 5 C/T drug Oxaliplatin (85mg/m2 ) in D5W 250ml IVD 2hr 150 mg IVD 6hr Desensitization Leucovorin (400mg/m2 ) in D5W 250ml IVD 2hr 700 mg 680 mg 5-FU (2400mg/m2 ) in D5W 500ml IVD 46hr pump 4200 mg 4150 mg 4100 mg Long-term medication MgO 250mg tid Bisacodyl 10mg hs Morphine 5mg q4h Naproxen 250mg bid Estazolam 2mg hs Chlorpromazine 50mg prn 1st HSR
  • 16 Which is the culprit drug ? Diphenhydramine Dexamethasone Metoclopramide Granisetron Oxaliplatin Leucovorin 5-FU ADR FOLFOX s/p FOLFIRI + Bevacizumab (11/29-01/14) Premedication Diphenhydramine Dexamethasone Metoclopramide Granisetron Atropine C/T drug Irinotecan Leucovorin 5FU Bevacizumab
  • 懷疑藥品 (包括西藥及中藥) 學名/商品名 含量/劑型 給藥 途徑 劑量頻率 起迄日期 用藥原因 可疑 藥品 Oxaliplatin (Eloxatin®) 50mg/vial IVD 150mg 102/02/01- 05/06 Rectal cancer 併用 藥品 Diphenhydramine Dexamethasone Metoclopramide Granisetron 30mg/amp 5mg/amp 10mg/amp 3mg/amp IVD IVD IVD IVD 1amp QD 2amp QD 1amp Q8H 1amp QD 102/02/01- 05/06 102/02/01- 05/06 102/02/01- 05/06 102/02/01- 05/06 Antiemetics (before C/T) 廠牌/批號 效期 26. 曾使用同類藥品之經驗  是  否  無法得知 藥品︰Oxaliplatin 不良反應︰hypersensitivity reaction 27. 停藥後不良反應是否減輕  是  否 無法得知 28. 再投藥是否出現同樣反應  是  否 無法得知 Sanofi-Aventis Unknown Deutschland Gmb 29. 是否同時使用  中草藥  西藥  健康食品  其他: 若有同時使用,請填入併用藥品內 17
  • Outline Oxaliplatin induced hypersensitivity reaction  Incidence and clinical features  Pathophysiology  Management ADR evaluation Case discussion Take home message  Patient evaluation  Treatment strategies
  • 19 Oxaliplatin  Pharmacological Properties  Third-generation platinum derivative, an alkylating agent  Covalently binds to DNA forming cross-links which inhibit DNA replication and transcription, resulting in cell death  Cell-cycle nonspecific  Indication Micromedex, Uptodate Expert Opin Drug Saf. 2006 Sep;5(5):687-94. [(1R,2R)-cyclohexane-1,2-diamine] (ethanedioato-O,O')platinum(II) FDA-labeled In combination with 5-FU/leucovorin • Stage III colon cancer, adjuvant • Metastatic colorectal cancer, first-line Unlabeled Esophageal cancer, gastric cancer, hepatobiliary cancer, non-hodgkin's lymphoma, ovarian cancer, pancreatic cancer, testicular cancer
  • 20 Oxaliplatin Product Information: ELOXATIN ®. Sanofi-Aventis U.S. LLC, Bridgewater, NJ, 2011 Drugs 2000; 60(4):895-924. Common Side Effects (>10%) Hematologic Anemia, thrombocytopenia, leukopenia, lymphopenia Immunologic Allergic reaction (skin rash, conjunctivitis, rhinitis) Neurologic Peripheral neuropathy (dose limiting), dysgeusia, headache Respiratory Dyspnea, cough Gastrointestinal N/V, diarrhea, abdominal pain, constipation, anorexia, stomatitis Musculoskeletal Back pain Other Fatigue, fever, hepatic enzyme increase Clinical trials & post marketing experience Pharmacokinetics Distribution Vd: 440 L Protein binding: >90% (irreversible binding) Metabolism Nonenzymatic biotransformation, rapid and extensive Excretion Urine: 54%; feces: 2% Elimination Half Life T1/2α: 0.43 h, T1/2β: 16.8 h, T1/2γ: 391 h
  • 21 Oxaliplatin-associated hypersensitivity reactions  Incidence  Rising incidence as a result of increasing clinical use  Usually are mild, but life-threatening anaphylactic reactions can occur Expert Opin Drug Saf. 2006 Sep;5(5):687-94. Met Based Drugs. 2010;2010. pii: 207084. Semin Radiat Oncol. 2003 Jul;13(3):176-81. CTCAE = Common Toxicity Criteria for Adverse Events HSR = hypersensitivity reaction Grading of Hypersensitivity Reactions (CTCAE, v3.0) Grade 1 Transient flushing or rash, drug fever < 38°C Grade 2 Rash, flushing, urticaria, dyspnea, drug fever > 38°C Grade 3 Symptomatic bronchospasm, with or without urticaria; parenteral medication indicated; allergy-related edema/angioedema; hypotension Grade 4 Anaphylaxis Grade 5 Death Overall Grade 3-4 10-18.9% 1-2% 
  • 22 Clinical features:  Retrospectively analyzed 308 cases of hypersensitivity reaction related to oxaliplatin  76% patients with colorectal cancer (81% metastatic, 19% adjuvant)  Regimen: FOLFOX (Oxaliplatin 85-130 mg/m2 IVD 2hours) Mild reaction (n = 195; 63%) Severe reaction (n = 113; 37%) Symptoms Flush, localized skin rash and itching (particularly on palms and soles), fever, chills, nausea, vomiting, abdominal pain, malaise severe erythema, angioedema, bronchospasm, laryngospasm tachycardia, hypotension Initial onset Mostly after 6th course, median 9th (range 1-24) Time of onset Either upon completion of oxaliplatin infusion or during the next few hours Within 5–10 min of drug infusion Outcome Reversible upon oxaliplatin withdrawal and symptomatic treatment (within minutes or hours) A 10-year experience in a single institute Oncology 2009;76:36–41
  • 23 Pathophysiology  Most oxaliplatin HSR seem to be IgE-mediated type I reactions 1. Expert Opin Drug Saf. 2006 Sep;5(5):687-94. 2. Met Based Drugs. 2010;2010. pii: 207084. 3. Ann Oncol. 2000 Apr;11(4):497. 4. Jpn J Clin Oncol. 2009 Sep;39(9):616-20. 5. Ann Oncol. 2001 Jan;12(1):132-3. Reported possible mechanism of oxaliplatin allergic reactions Type of reaction Onset Mediators Symptoms related Ref I early IgE Itching, rash, hypoxemia, anaphylactic reactions 1,2 II (Cytotoxic) late IgG, IgM, Hemolysis, thrombocytopenia 3 III (Immune complex) late IgG Chronic urticaria, joint pain, proteinuria 4 Idiosyncratic reaction late nonimmune-mediated cytokine release (IL-6, TNF-a) Chills, fever, N/V, abdominal cramps, diarrhea, chest tightness, hypotension 5  Symptoms of our patient 1st HSR Dyspnea, erythema and generalized itching, 焦躁坐立不安, 流鼻水 2nd HSR 全身癢,前胸臉頰皆有紅疹情形,煩躁不安 3rd HSR 全身發紅起紅疹,雙手、雙腳及後背癢,大腿內側尤其明顯
  • Type I hypersensitivity reaction Trends Immunol. 2008 Dec;29(12):633-42. Allergen re-exposed Oxaliplatin associated type I HSR • Need of multiple infusions for sensitization • Rapid onset symptoms • Positive intradermal skin tests in majority of patients with history of oxaliplatin hypersensitivity 24 Sensitization
  • 25 Risk factors Oncology 2009;76:231–238 USA, N=29/247 (11.7%) Female sex Female 17.2% p= 0.01 Male 6.4% Younger mean age With HSR 54.9±12.5 p= 0.02 Without HSR 60.4±12.4 Use of oxaliplatin as salvage therapy Initial 9.1% p=0.01 2nd line or higher 23.9% J Formos Med Assoc 2010;109(5):362–368 Taiwan, N=43/383 (12.7%) Premedication with 5 mg dexamethasone 5 mg vs. ≥ 10mg HR 2.094 (1.141–3.843) Higher oxaliplatin dose 3rd quartile vs. 1st quartile HR 1.024 (1.007–1.040) Oncology 2010;79:136–143 Japan, N=45/223 (20.1%) Younger age < 60 y vs. ≥ 60 y OR 3.5 (1.4–8.6) Oxaliplatin-free interval in stop-and-go FOLFOX Yes vs. no OR 3.1 (1.2–7.7) Stop-and-go strategy • To reduce neurotoxicity • Preplanned withdrawal of oxaliplatin after six cycles and reintroduction of FOLFOX at the time of disease progression   
  • 26 Management of HSR 1. Stop oxaliplatin infusion immediately 2. Administer: • I.V. Antihistamines • Low-dose corticosteroids 3. In case of a more severe reaction (dyspnea, laryngospasm, bronchospasm) • Oxygen, bronchodilators • High dose steroids (hydrocortisone 100-1000 mg) 4. In case of hypotension or airway obstruction symptoms • Epinephrine 5. Monitoring until symptoms resolve completely or for several hours later in case of severe hypersensitivity Expert Opin Drug Saf. 2006 Sep;5(5):687-94. Met Based Drugs. 2010;2010. pii: 207084
  • Outline Oxaliplatin induced hypersensitivity reaction  Incidence and clinical features  Pathophysiology  Management ADR evaluation Case discussion Take home message  Patient evaluation  Treatment strategies
  • 28 Patient evaluation Japan 21/125 (17%) 60 (42-78) 19% / 15% - 9 (2-15) - - Gr1-2 (76%) 1. Oncology 2009;76:231–238 2. Ann Oncol. 2006 Feb;17(2):259-61. 3. J Formos Med Assoc. 2010 May;109(5):362-8. USA 1 Hong kong 2 Taiwan 3 Our patient N (incidence) 29/247 (11.7%) 27/180 (15%) 47/383 (12.3%) - Age (yr) 54.9 (42-67) - 61 (21-91) 34 Sex (F/M) 17.2% / 6.4% - - M Line of therapy Salvage 24.9% Initial 9% Salvage 19.6% Initial 10.2% - Salvage Cycles (median) 7 (1–11) 8.5 (1-18) 10 (2-19) 85% after 6th cycle 5 Onset (min) 70 (10-240) 55.6% pt < 60 40 (5-215) 88.7% pt < 120 1st : 34 2nd : 45 Most common symptoms Flushing (52%) Urticarial (52%) Dyspnea (24%) Rash (44%) Itchiness (33%) Fever/chills (29%) Flushing (29%) Chest tightness (18%) Cutaneous (70%) Respiratory (30%) Fever (25%) HTN (18%) Chills (18%) Erythema Itching Dyspnea 焦躁坐立不安 流鼻水 Severity Gr1-2 (86%) Gr1-2 (85%) Gr1-2 (90.7%) 1 pt died of anaphylactic shock Gr 2
  • 29 Treatment Strategies Expert Opin Drug Saf. 2006 Sep;5(5):687-94. Oncology 2009;76:36–41 Modereate-Severe reactions Respiratory disturbance, cardiovascular reaction, skin reactions, angioedema Life-threatening reactions Anaphylactic shock, cardiac arrest No standardized protocol for reintroduction was established • Infusion rate and premedication • Desensitization protocols • Alternative treatment options Definitive drug discontinuation Mild-moderate reactions Localized skin rash, itching, fever, chills, N/V, abdominal pain, malaise Evaluate the risk and benefit of reintroduce 4/19 2nd HSR 5/06 3rd HSR
  • 30 Infusion rate and premedication  Patients with mild to moderate hypersensitivity reactions to oxaliplatin may be able to tolerate rechallenge with  Premedication with antihistamine, steroids  Increase infusion duration J Support Oncol 2008;6:373–378 Expert Opin Drug Saf. 2006 Sep;5(5):687-94. 30 pt with Gr1/2 HSR A retrospective study in a single institute in Japan Rechallenge with secondary prevention • Premedication: (30 min before oxaliplatin infusion) Dexamethasone 20 mg IV Diphenhydramine 50 mg PO Famotidine 40 mg PO • Prolong infusion (2 4hr) Successful prevention ≥ 2 courses 19 (63.3%) Failure 11 (36.7%) Severity on 2nd HSR • Equivalent: 9 (81.8%) • Worse: 2 (18.2%) Premedications cannot prevent all HSR, and mild reactions may escalate to severe reactions Our patient- 4/19 2nd HSR Dexamethasone 10 mg Diphenhydramine 30 mg Ranitidine 50mg Prolong infusion (2 6hr)
  • Reported desensitization protocols for oxaliplatin 1. Oncologist2004; 9:546–549 2. Clin Transl Oncol. 2013 Mar;15(3):219-25. 3. Clin Colorectal Cancer. 2009 Mar;8(2):106-9 4. Anticancer Drugs. 2004 Jul;15(6):605-7. Ref n Premedication Steps Duration Success rate 1 1 (Gr3) • Dexamethasone PO for 1 day • Diphenhydramine IVD Hydrocortisone 100 mg IVD before oxaliplatin 5 steps From 1 : 10000 to 1 : 1 8 h 100 % 2 53 (Gr1-3) • Corticosteroids 1mg/kg/d Ranitidine 300mg/d Cetirizine 20mg/d Montelukast 10mg/d For 1 day and 30 min before oxaliplatin 13 steps From 1: 10000 to 1 : 1 3-4 h 89 % 3 3 (Gr1-2) • None 13 steps From 1 : 100000 to 1 : 1 8 h 100 % 4 1 (Gr2) • Diphenhydramine 50mg PO QID for 1 day • Diphenhydramine 30 mg IVD Dexamethasone 5mg IVD before oxaliplatin Continuous fixed rate (0.15 mg/ml) 24 h 100 % Administer premedication Escalating concentrations Prolonged infusion
  • 5 steps desensitization protocols 32 Ref n Premedication Steps Duration Success rate 1 1 (Gr3) • Dexamethasone PO for 1 day • Diphenhydramine IVD Hydrocortisone 100 mg IVD before oxaliplatin 5 steps From 1 : 10000 to 1 : 1 8 h 100 % Our patient Premedication (IVD before C/T) Diphenhydramine 30 mg IVD Dexamethasone 20 mg IVD Ranitidine 50 mg IVD Hydrocortisone 100 mg IVD 4hr (bag5 30min前給) C/T drug Conc (mg/ml) Oxaliplatin 0.014 mg in D5W 100ml IVD 1hr [bag 1] 0.00014 Oxaliplatin 0.14 mg in D5W 100ml IVD 1hr [bag 2] 0.0014 Oxaliplatin 1.4 mg in D5W 100ml IVD 1hr [bag 3] 0.014 Oxaliplatin 14 mg in D5W 100ml IVD 1hr [bag 4] 0.14 Oxaliplatin 126 mg in D5W 100ml IVD 4hr [bag 5] 1.26 HSR: 35ml Oncologist2004; 9:546–549
  • 34 Desensitization protocols  Disadvantages  Time-consuming  Inconvenience of the patient  Burden of the oncology departments  Risks and benefits must be carefully weighed before offering desensitization procedure  Patients should be informed of the danger as there is still risk of anaphylaxis, or even death during the rechallenge  Indicated especially for patient who  Have been benefited by the drug  No alternative treatment options Expert Opin Drug Saf. 2006 Sep;5(5):687-94. Oncology 2009;76:36–41. Met Based Drugs. 2010;2010. pii: 207084
  • 1739 2752 3373 3042 3855 3545 3517 2782 3149 3028 3583 1000 1500 2000 2500 3000 3500 4000 CEA.(ng/mL) 11/1 12/14 1/4 1/21 2/6 2/23 3/12 4/3 4/13 4/30 5/13 Alternative treatment options ? 35 10/26 11/29 1/14 2/01 5/06 2013 765 ADR 2012 FOLFIRI + Bevacizumab (3 cycles) FOLFOX (7 cycles) Diagnosis in progression Rectal cancer with liver metastasis, cardiac seeding • T4N2M1 stage IV • KRAS mutation: G12D
  • Alternative treatment options ? Treatment sequencing options for patients with metastatic colorectal cancer who can tolerate intensive therapy Initial therapy FOLFIRI + bevacizumab Therapy after 1st progression • FOLFOX or CAPOX • Irinotecan + cetuximab (WT KRAS only) • Cetuximab or panitumumab (WT KRAS only) Therapy after 2nd progression • Irinotecan + cetuximab (WT KRAS only) • Cetuximab or panitumumab (WT KRAS only) • Regorafenib Therapy after 3rd progression • Regorafenib (if not given previously) • Clinical trial • Best supportive care 34 y/o, male • T4N2M1 stage IV • KRAS mutation: G12D 36 WT: wild-type Approval FDA 2012/09 TFDA 2013/10
  • 37 Regorafenib tab 40mg/tab (Stivarga) Mechanism of Action  A multikinase inhibitor, involved with tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment 適應症  適用於治療先前曾接受下列療法的轉移性大腸直腸癌患者,療法包括 fluoropyrimidine-、oxaliplatin-、irinotecan-為基礎的化療,和anti-VEGF等療法  160 mg QD PO for the first 21 days of each 28-day cycle Common side effect  Asthenia/fatigue, hand-foot skin reaction, diarrhea, decreased appetite, hypertension, mucositis… Micromedex, uptodate NCKUH 專案藥品 Severe and sometimes fatal hepatotoxicity has been observed in clinical trials
  • Our patient 39 1st HSR 2nd HSR 3rd HSR Protocol Standard Rechallenge Desensitization Premedication Diphenhydramine 30mg Dexamethasone 10 mg Diphenhydramine 30mg Dexamethasone 10 mg Ranitidine 50 mg Diphenhydramine 30mg Dexamethasone 20 mg Ranitidine 50 mg Infusion duration 2 h 6 h 8 h Onset 34 min 45 min 4 h 50 min Dosage 38.4 mg 19.2 mg 50.6 mg Symptoms Dyspnea, erythema and generalized itching, 焦躁 坐立不安, 流鼻水 全身癢,前胸臉頰皆有 紅疹情形,煩躁不安 全身發紅起紅疹,雙手、 雙腳及後背癢,大腿內 側尤其明顯
  • 成大醫院藥物不良反應評估表(1) 病患基本資料 床號:11B** 病歷號:******** 姓名: ○○○ 性別:男 該不良反應報告日期與實際發生日期是否相同? □ 否 ■ 是 不良反應實際發生日期:2013/04/04 出生年月日: 1979/05/06 (34歲) 診斷:oxaliplatin hypersensitivity 促成該不良反應的危險因素: ■ 否 □ 是,危險因素為: 是否與藥物交互作用相關:■ 否 □ 是,品項為: 該不良反應的臨床表徵:Hypersensitivity reaction ■ Anaphylactic □ GI □ Metabolic □ Cardiovascular □ Hematologic □ Nephrotoxicity □ CNS □ Hepatic □ Other ■ Dermatologic □ Infection 40
  • 藥物不良反應相關性評估 Naranjo Score Yes No Do not know 1. 此不良反應是否有確定的研究報告? +1 0 0 2. 此不良反應是否發生於服藥之後? +2 -1 0 3. 當停藥或使用此藥之解藥,不良反應是否減輕? +1 0 0 4. 再次服用此藥,同樣的不良反應是否再度發生? +2 -1 0 5. 有沒有其他原因(此藥以外)可以引起同樣之不良反應? -1 +2 0 6. 當給予安慰劑時,此項不良反應是否也會再度發生? -1 +1 0 7. 此藥物的血中濃度是否達到中毒劑量? +1 0 0 8. 對此病人而言,藥物劑量與不良反應的程度是否成正向關係? +1 0 0 9. 病人過去對同樣或類似藥物是否也產生同樣的不良反應? +1 0 0 10.此不良反應是否有任何客觀證據可證實? +1 0 0 總分 10 ;判斷屬於下列何者: ■  9分,確定; □ 5-8分,極可能; □ 1-4分,可能; □  0分,存疑 41
  • 成大醫院藥物不良反應評估表(2) 可能性評估: ■ 確定 ( 9分) □ 極可能(5-8分) □ 可能(1-4分) □ 存疑(0分) 嚴重程度: □ 死亡 □ 危及生命 □ 永久性殘疾 □ 先天性畸形 ■ 需做處置以防永久性傷害 □ 導致住院 □ 增加住院日 □ 需額外的醫療處置 □ 自行緩解 藥物不良反應型態: □ Type A (Pharmacological) ■ Type B (Idiosyncratic) 報告來源: □ 經由藥師訪視、住院藥品調配單或病歷記錄 □ 經由其他的預警因素如:緊急處方、實驗數值、報表或電腦 查詢等 ■ 其他醫事人員通告如:護士、醫師等 □ 經由其他醫事人員填寫之藥物不良反應報告表 42
  • 43 Take home message Incidence Symptoms • Overall 10-18.9%, Grade 3-4 1-2% • Variable (Flush, skin rash, itching, dyspnea, fever, nausea, tachycardia, hypotension, anaphylaxis…) Initial onset • Mostly after 6th cycles Time of onset Can it be reintroduced ? • Minutes-hours Yes (except life-threatening reactions) • Premedication • Prolong infusion time • Desensitization protocol  Cannot prevent all HSR  Mild reactions may escalate into severe reactions  Patients should be informed of the risk Possible Risk factors • Female sex • Younger age • Oxaliplatin as salvage therapy • Lower dexamethasone dose • Higher oxaliplatin dose • Oxaliplatin-free interval
  • 44 Photo by Magdalena Ginalska
  • 45 一項隨機分配、雙盲、安慰劑對照之第III期試驗,針對標準治療後 病情惡化的轉移性大腸直腸癌(CRC)亞洲受試者,比較regorafenib併 用最佳支持性照護(BSC)相對於安慰劑併用BSC之療效