Toxicity of Cytotoxic Agents and of Targeted Agents. Jong Gwang Kim MD, PhD Kyungpook National University

Transcription

1 Toxicity of Cytotoxic Agents and of Targeted Agents Jong Gwang Kim MD, PhD Kyungpook National University

2 Contents Toxicity of Cytotoxic agents Toxicity of Targeted agents

3 Action sites of cytotoxic agents DNA synthesis Antimetabolites DNA Alkylating agents DNA transcription DNA duplication Cellular level Intercalating agents Mitosis Spindle poisons

4 Side effects of chemotherapy Mucositis Alopecia Nausea/vomiting Diarrhea Cystitis Sterility Myalgia Neuropathy Pulmonary fibrosis Cardiotoxicity Local reaction Renal failure Myelosuppression Phlebitis

5 Side effectsof chemotherapy Immediate Early Delayed Late (hours - days) (days - weeks) (weeks- months) (months - yrs) Extravasation Myelosuppression Cardiotoxicity Second cancer Emesis Mucositis Lung fibrosis Encephalopathy Hypersensitivity Alopecia P. Neuropathy Sterility Tumour lysis Cystitis Hepatotoxicity Teratogenicity Skin toxicity Nephrotoxicity

6 Common agents in CRC Agents 5-Fluorouracil Capecitabine Irinotecan Oxaliplatin Side effects Cytopenia,diarrhea, hand-foot syndrome, stomatitis, alopecia, etc Hand-footsyndrome, diarrhea, stomatitis, etc Cytopenia, diarrhea, emesis, alopecia, etc Cytopenia, neuropathy, emesis, etc

7 Common agents in CRC Agents 5-Fluorouracil Capecitabine Irinotecan Oxaliplatin Side effects Cytopenia,diarrhea, hand-foot syndrome,stomatitis, alopecia, etc Hand-footsyndrome, diarrhea, stomatitis, etc Cytopenia, diarrhea, emesis, alopecia, etc Cytopenia, neuropathy, emesis, etc

8 5-fluorouracil + LV regimens Mayo Clinic regimen -IV bolus for 5 days, 4 weeks interval de Gramont regimen - LV 2-hour infusion, days 1-2 -IV bolus 5-FU & 22-hour infusion, day weeks interval EORTC AIO regimen - 24-hour infusion 5-FU weekly, week 1-6 -with or without 2-hour infusion LV -7 weeks interval

9 Continuous versus Bolus regimen (compared to Mayo Clinic regimen) de Gramont (n=348) EORTC AIO (+LV, n=498) Response rate (%) 32.6/ /11.5 P<0.004 P=NS Time to Progression (month) Overall Survival (month) 6.3/5.0 P= /13.0 P=NS 6.4/4.1 P= /12.0 P=NS

10 Incidence of side effects (grade III/IV)

11 5-FU + LV Continuous versus Bolus regimen -Meta-analysis - Six trials Bolus Continuous P value : 1,219 patients Response rate (%) <0.002 Overall survival (months) < 0.04 Grade III/IV neutropenia (%) 31 4 < Hand-foot syndrome (%) < Meta-analysis Group in Cancer, JCO 1996

12 Preference according to Country

13 Common agents in CRC Agents 5-Fluorouracil Capecitabine Irinotecan Oxaliplatin Side effects Cytopenia,diarrhea, hand-foot syndrome, stomatitis, alopecia, etc Hand-footsyndrome, diarrhea, stomatitis, etc Cytopenia, diarrhea, emesis, alopecia, etc Cytopenia, neuropathy, emesis, etc

14 Hand-Foot Syndrome Also known as palmar plantar erythrodysesthesia (PPE) Skin lesions begin as erythema/edemaof the palms or soles and is associated with sensitivity to touch or paresthesia Can progress to desquamationof the affected areas and significant pain Incidence : 45-68% of patients treated with capecitabine

15 Pathogenesis Unclear: damaged deep capillaries in the soles of the feet and palms of the hands -> leading to a COX inflammatory-type reaction : related to enzymes involved in the metabolism of capecitabine(thymidine phosphorylase& dihydropyrimidine dehydrogenase) Formulation of drugs and duration of exposure can impact the incidence 5-FU bolus lower than CIVI and capecitabine

16 Hand foot syndrome: Grading Grade Signs and symptoms 1 Minimal skin changes or dermatitis (eg, erythema) without pain 2 Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function 3 Skin changes with pain, interfering with function Cancer Therapy Evaluation Program Common Toxicity Criteria for Adverse Events, version 3.0, June 2003 Scheithaur, W, Blum, J. Coming to grips with and-foot syndrome: Insights from clinical trials evaluating capecitabine. Oncology 2004; 18:1161

17 Treatment No proven preventive therapy Pyridoxine (vitamin B6): not effective (Kang et al JCO 2010) Celecoxib reported to reduce incidence Management largely symptomatic with reduction of drug doses or interruption where appropriate Emollients and protective gloves can be helpful

18 Common agents in CRC Agents 5-Fluorouracil Capecitabine Irinotecan Oxaliplatin Side effects Cytopenia,diarrhea, hand-foot syndrome, stomatitis, alopecia, etc Hand-footsyndrome, diarrhea, stomatitis, etc Cytopenia, diarrhea, emesis, alopecia, etc Cytopenia, neuropathy, emesis, etc

19 Timing of adverse events delayed diarrhea Neutropenia nadir Cholinergic syndrome Med. duration of neutropenia D1 D5 D8 D16

20 Delayed diarrhea: Characteristics Defined by its onset more than 24 h after irinotecan infusion Secretory mechanism with exudative process Median time of onset : 6 days If diarrheaoccurs, it is mainly at the beginning of treatment Decreased incidence after the first three cycles

21 Delayed diarrhea: Management Should be promptly and properly managed Patient information : need for early loperamide dosing and a high fluid intake Loperamide administration Oral rehydration if necessary *Loperamide should not be used as prophylactic treatment

22 Common agents in CRC Agents 5-Fluorouracil Capecitabine Irinotecan Oxaliplatin Side effects Cytopenia,diarrhea, hand-foot syndrome, stomatitis, alopecia, etc Hand-footsyndrome, diarrhea, stomatitis, etc Cytopenia, diarrhea, emesis, alopecia, etc Cytopenia, neuropathy, emesis, etc

23 Oxaliplatin induced neurotoxicity : two distinct forms Acute, transitory sensory neuropathy Chronic, cumulative sensory neurotoxicity

24 Acute neuropathy Common, occurring in up to 80-90% of patients Generally mild, short-lived, completely reversible May appear at first cycle Often cold-induced Depending on dosing schedule (infusion rate), not dose limiting Clinical signs dysesthesia, paresthesia at: distal extremities perioral, oral, pharyngolaryngeal areas occasionally muscular contractions

25 Proposed pathomechanism of Na + influx inhibition oxalate forms chelate with Ca 2+ EXTRA oxaliplatin Membrane Na + INTRA ATP ATP Ca 2+ oxalate Dach- Pt

26 Cumulative sensory neurotoxicity Frequency of grade 3/4 sensory neurotoxicity -in 10-15% after a cumulative dose of mg/m 2 (about 5-6 months of treatment) -in 50% at 1170 mg/m 2 (Brienza et al., ASCO 1995) Generally reversible or improved after tx discontinuation Median time to recovery from grade 3: 13 weeks (de Gramont et al., JCO 2000) Purely sensory neurotoxicity without involvement of motor neurons, no ototoxicity

27 FOLFOX4: onset of neurotoxicity and tumor response Clinical decision 0.8 Probabilit ty Onset of response Onset of grade 3 neuropathy weeks of treatment with FOLFOX4 Haller 2000

28 MOSAIC: peripheral sensory neuropathy Paresthesias (NCI version 1) FOLFOX4 arm Per patient One year 18 months (n=1108) after ctx after ctx Grade % 70.5% 76.3 % Grade % 23.6 % 19.8 % Grade % 4.8 % 3.4 % Grade % 1.1 % 0.5 % G3: 18% in patients with 1020 mg/m 2 median oxaliplatin dose-intensity: 81% (840 mg/m 2 ) Andre et al, NEJM 2004

29 Recover ry probability Duration of grade 3 neuropathy PARTIAL resolution (Gr<3) COMPLETE resolution (Gr 0) Weeks De Gramont GI ASCO 2005

30 Strategies for prophylaxis or treatment of oxaliplatin neurotoxicity Stop and Go strategy (e.g. OPTIMOX) Stop after predefined cumulative oxaliplatin dose or when sensory neurotoxicity of certain grade develops Go palliative setting when sensory neurotoxicity has regressed or when oxaliplatin therapy requires to stop tumor progress Neuromodulatory agents Ca + Mg + /gabapentin/carbamazepine/venlaflaxine Glutathione/BNP-7787 (Tavocept) Xaliprodene adjuvant & palliative setting

31 Retrospective analysis of CaMg to prevent oxaliplatin-induced neurotoxicity 161 patients (oxaliplatin-based CTx) Ca 2+ gluconate1 g + Mg 2+ sulfate 1 g before and after oxaliplatin (n=96) No Ca 2+ /Mg 2+ (n=65) Safety Treatment duration Efficacy Gamelin et al, Clin Cancer Res 2004

32 Neurotoxicity as reason for treatment 35 discontinuation % of drop outs for neurotoxicity CaMg no CaMg Oxaliplatin dosage (mg/m 2 ) Gamelin et al, Clin Cancer Res 2004

33 100 Duration of treatment with CaMg 80 no Ca 2+, Mg 2+ + Ca 2+, Mg 2+ % of patie ents Duration of treatment (cycles) Gamelin et al, Clin Cancer Res 2004

34 Efficacy is not reduced with CaMg % of pat tients CR PR SD PD Treatment efficacy CaMg n=42 no CaMg n=43 Gamelin et al, Clin Cancer Res 2004

35 Contents Toxicity of Cytotoxic agents Toxicity of Targeted agents

36 Targeted agents Mab Receptor STEP cell membrane Post-receptor STEP G-protein linked receptors Enzyme-lined receptors Receptor tyrosine kinase Tyrosine kinase associated receptors Serine/Threonine kinase receptors Nuclear receptors TKI nucleus Cell Cycle Ligand

37 Therapeutic options in cancer Monoclonal Antibodies Tyrosine Kinase Inhibitors Chemotherapy Radiation Specificity for a target Absolute Specificity Variable Specificity Low Specificity Low Specificity Toxicity Low Low/Moderate High Moderate MTD Evaluated* Pending Yes Yes Yes Administration IV IV/Oral IV/Oral Local Half-life Days to weeks Hours to days Hours to days NA *Does not include radio-labeled or toxin-conjugated monoclonal antibodies

38 Agents Common agents in CRC Side effects Bevacizumab Cetuximab/panitumumab Hypertension, bleeding, proteinuria, thromboembolism, wound complication,bowel perforation, etc Skin toxicity, infusion-related reactions, etc

39 Agents Common agents in CRC Side effects Bevacizumab Cetuximab/panitumumab Hypertension, bleeding, proteinuria, thromboembolism, wound complication,bowel perforation, etc Hypersensitivity,skin toxicity, etc

40 Hypertension Most common side effect All grades: 22-32% Grade 3/4: 11-16% most are grade 3: in BP that require initiation of oral antihypertensive tx or a change in existing antihypertensive tx 0.7% discontinue bevacizumab d/t HT Possible dose relationship 3/35 (5mg/kg) vs 8/32 (10mg/kg) Calcium channel blocker, ACEI Measure BP every 2-3 weeks

41 BRiTE*: Hypertension at baseline and after treatment with bevacizumab plus chemotherapy Patients (%) 100 Baseline HTN No HTN Patients (%) No change Increased HTN Post bevacizumab+ chemotherapy Patients (%) 100 *Non-randomised, observational trial; HTN = hypertension No change De-novo HTN Kozloff, et al. ASCO GI 2007

42 Bleeding Patients treated with bevacizumab may have an increased risk of developing tumour-associated haemorrhage Minor epistaxis (mostly grade 1): 20-40% Grade 3/4 bleeding: % CNS hemorrhage not fully evaluated, d/t exclusion of patients with CNS metastasis patients with untreated CNS metastasis: contraindication

43 Bleeding NSCLC life-threatening pulmonary hemorrhage: 9% squamous cell ca: most at risk Patients with bleeding tendency, reciveing anti-coagulation : should be treated with caution

44 Common event: 20-40% Proteinuria majority: grade 1 proteinuria improves after discontinuation Grade 3 proteinuria and nephrotic syndrome rare, events are possibly linked to hypertension Recommendations proteinuria should be monitored by dipstick urinalysis prior to starting and during therapy therapy should be stopped in patients with grade 4 proteinuria (nephrotic syndrome)

45 Thromboembolism Overall/venous thromboembolism: not increased Arterial thromboembolism: 2-fold Pooled analysis of 5 clinical trials 3.8% (chemo + bev) vs 1.7% (chemo alone) mortality d/t ATE: 0.8% vs 0.4% (CVA, TIA, SAH, MI) higher risk with HTN, proteinuria, age 65, history of ATE Recommendation patients who develop ATEs should discontinue bevacizumab

46 Time to onset of any ATE during therapy: pooled analysis 1.0 Proport tion event-free Chemotherapy/control Chemotherapy/bevacizumab Time to first arterial event (months) Patients at risk by timepoint Months Control Chemotherapy/Avastin Uncorrected for uneven time on treatment and shorter follow-up for control patients Skillings JR, et al. J Clin Oncol 2005;23(June 1 Suppl.):196s (Abstract 3019)

47 Wound healing Bevacizumab - may adversely affect the wound healing process -uncommonly lead to wound healing complications in the previous studies 1,2 Bevacizumab therapy should be discontinued in patients who experience wound healing complications during therapy until the wound is fully healed at least 4 weeks following major surgery or until the surgical wound is fully healed at least 4 weeks prior to elective surgery 1 Hurwitz H, et al. J Clin Oncol 2004;22(July 15 Suppl.):Abstract Scappaticci F, et al. J Clin Oncol 2004;22(July 15 Suppl.):Abstract 3530

48 BEAT: Surgery with curative intent did not increase wound-healing complications Grade 3 4 AE or SAE n=225 (%) Special interest for Avastin 1 Hypertension Proteinuria Bleeding Wound-healing complications ATEs GI perforation Surgical-related complications 2 Wound-healing complications Bleeding AE = adverse event; SAE = serious AE ATE = arterial thromboembolic event; GI = gastrointestinal Cassidy, et al. EMCCC Cassidy, et al. ASCO 2008

49 GI perforation Uncommon but life-threatening event % of patients with mcrc treated with bevacizumab 1 3 potential risk factor 5 : peptic ulcer disease, diverticulitis, recurrent tumor at the site of perforation, history of abdominal irradiation, abdominal carcinomatosis, or obstruction Recommendations caution should be exercised bevacizumab therapy should be permanently discontinued in patients who develop GI perforation 1 Kabbinavar FF, et al. J ClinOncol2005;23: Giantonio BJ, et al. J ClinOncol2005;23(June 1 Suppl.):1s (Abstract 2) 3 Hurwitz H, et al. N EnglJ Med 2004;350: Kozloff M, et al. J ClinOncol2005;23(June 1 Suppl.):262s (Abstract 3566)

50 Bevacizumab: grade 3 4 bevacizumab-related serious AEs (NO16966 and BEAT*) NO16966 Bleeding, n (%) WHC, n (%) GI perforation, n (%) Hypertension, n (%) ATE, n (%) FOLFOX or XELOX + placebo (n=675) 8 (1.2) 2 (0.3) 2 (0.3) 8 (1.2) 7 (1.0) FOLFOX or XELOX + bevacizumab (n=694) 13 (1.9) 1 (0.1) 4 (0.6) 26 (3.7) 12 (1.7) BEAT ITT population (n=1914) 61 (3.2) 20 (1.0) 34 (1.8) 97 (5.1) 24 (1.3) BEAT Patients undergoing curative intent metastasectomy (n=225) 1 (0.4) 4 (1.8) 5 (2.2) 16 (7.1) 3 (1.3) Any grade 3 (1.3) Any grade 11 (4.9) *Non-randomized, observational study GI = gastrointestinal; WHC = wound healing complications Okines, et al. BJC 2009

51 Agents Common agents in CRC Side effects Bevacizumab Cetuximab/panitumumab Hypertension, bleeding, proteinuria, thromboembolism, wound complication,bowel perforation, etc Skin toxicity, infusion-related reactions, etc

52 EGFR inhibitor-induced skin reactions Acne-like rash Post-inflammatory effects Dry skin Fissura Pruritus Paronychia Description of severe cases Pictures provided by S Segaert and E Van Cutsem (Leuven, Belgium).

53 EGFR: mechanism of actionand activation in skin The EGFR - important for normal skin development and function -strongly expressed in keratinocytes in the sebaceous glands and in the epithelium of hair follicles Activation of EGFR in skin Proliferation Migration Keratinization Survival of keratinocytes Important during wound healing and maintenance of the epidermal barrier!

54 Inhibition of EGFRin skin Inhibition of EGFR in skin leads to: alteration of normal skin homeostasis a variety of pathological changes Thinning of the epidermis Disorganization of the follicles Folliculitis Acneiform eruptions Seborrheic dermatitis Paronychia

55 Gradingof skin rash NCI CTCAE v4.0

56 Cetuxiamb-related acne-like rash peaks in the first 2-3 weeks of treatment Intens sity Acne-like rash Approximately 14%of patients experience grade 3 acne-like rash Week

57 Correlation of rash and survival after treatment with cetuximab 12 (months) Survival CRC CRC CRC CRC Pancreatic SCCHN Study: BOND Saltz (2001) 1 Saltz (2004) 2 Cunningham Van Cutsem Xiong (2004) 5 Kies (2002) 6 (2004) 3 (2004) 4 No reaction Grade 1 Grade 2 Grade 3 1 Saltz et al. Proc ASCO Saltz et al. J Clin Oncol Cunningham D Van Cutsem E. N Engl J Med Van Cutsem et al. EORTC/NCI Geneva Xiong H et al. J Clin Oncol Kies et al. Proc ASCO 2002.

58 Management guideline Acne-like rash Post-inflammatory effects Dry skin Fissura Pruritus Paronychia Description of severe cases Topical anti-acne creams (drying effect) +/- oral antibiotics +/- antihistamines Grade 3: refer to dermatologist THERAPY SUGGESTIONS Emollients Antihistamine Topical steroid Hydrocolloid dressing or Propylene glycol +/- salicylic acid Anti-septic soaks Silver nitrate (pyogenic granuloma) Potthoff et al Ann Oncol 2011

59 Vitamin K Vitamin K: an activator of the EGFR pathway Vitamin K2 - biologically active form -synthesized in the liver from all the other K vitamins The use of vitamin K cream -can reduce skin toxicity

60 Study design: Topical vitamin K1 cream 79 patients with mcrcreceived weekly cetuximabplus chemotherapy premedication: H1 antagonist and corticosteroids Upon development of acne-like rash a -a cream containing urea and 0.1% vitamin K1 : topically twice daily Monitored weekly for 12 weeks a NCI CTCAE version 3 Ocvirk J, Rebersek M. WCGIC 2009 Poster PD0021

61 Results: Development of acne-like rash 69/79 patients (87%) developed an acne-like rash (any grade) median of 1.2 weeks (range, 1 4 weeks) Grade of rash developed after cetuximab infusion Patients with ras sh (%) Grade 1 Grade 2 Grade 3 No grade 4 rash Ocvirk J, Rebersek M. WCGIC 2009 Poster PD0021

62 Results: Effect of vitamin K1 cream on acne-like rash In all patients, the severity of the acne-like rash was reduced after twice-daily application of vitamin K1 cream median time to improvement: 1.2 weeks time to downstaging of the rash by <2grade: 2.3 weeks Ocvirk J, Rebersek M. WCGIC 2009 Poster PD0021

63 Cutaneous toxicities induced by EGFR inhibitors After one week of using vitamin K1 cream

64 Cutaneous toxicities induced by EGFR inhibitors After one week of using vitamin K1 cream

65 Results: Treatment exposure and safety Cetuximab dose reductions and treatment delays Grade 1/2 rash: no dose reductions or treatment delays required Grade 3 rash: 5/20 patients (25%) required a dose reduction Topical clindamycin was applied concomitantly in 12/20 and 3/38 patients with grade 3 and grade 2 rash, respectively 4 patients with grade 3 acne-like rash received systemic antibiotics Topical use of vitamin K1 cream was not associated with any toxicities Ocvirk J, Rebersek M. WCGIC 2009 Poster PD0021

66 Infusion-related reactions : MABEL post hoc analysis Pa atients (%) % Antihistamine alone (n=422) Incidence of IRRs 9.6% Antihistamine + corticosteroid (n=700) Grade 4 Grade 3 Grade 1/2 Grade 3/4 IRRs reported for 1% of patients (Grade 4: 1 pt) Most IRRs (59%): within 3 hours of cetuximab infusion Cetuximab treatment: may be restarted after grade 1 or 2 IRR Siena S, et al. Cancer 2010;116:

67 MABEL post hoc analysis: Premedication in relation to efficacy PFS and OS rates at 12 weeks, by premedication group Rate (%) PFS OS Antihistamine alone (n=422) Antihistamine + corticosteroid (n=700) Siena S, et al. Cancer 2010; 116(7):

68 Summary: Cytotoxic agnets in CRC Agents Side effects Management 5-Fluorouracil Cytopenia,diarrhea, hand-foot syndrome, stomatitis, alopecia, etc Capecitabine Hand-footsyndrome, diarrhea, stomatitis, etc Irinotecan Oxaliplatin Cytopenia, diarrhea, emesis, alopecia, etc Cytopenia, neuropathy, emesis, etc Dose reduction Dose reduction/interrupt ion, symptomatic tx Loperamide Stop & go, neuromodulatory agents

69 Summary: Targeted agents in CRC Agents Side effects Management Bevacizumab Hypertension, bleeding, proteinuria, thromboembolism, wound complication, bowel perforation, etc Caution!/monitori ng, discontinuation Cetuximab /panitumumab Skin toxicity, infusionrelated reactions, etc Topical agent (vitamin K cream)

70 Thank you for your time and attention!