Management of side-effects of anti-angiogenetic inhibitors in treating HCC

Transcription

1 Management of side-effects of anti-angiogenetic inhibitors in treating HCC Massimo Di Maio Clinical Trials Unit National Cancer Institute, Napoli

2 BCLC staging system and treatment strategy Di Maio, Roma AISF 2011 HCC Stage 0 PST 0, Child Pugh A Stage A C PST 0 2, Child Pugh A B Stage D PST > 2, Child Pugh C Very early stage (0) 1 HCC < 2 cm Carcinoma in situ Early stage (A) 1 HCC or 3 nodules < 3 cm, PST 0 Intermediate stage (B) Multinodular, PST 0 Advanced stage (C) Portal invasion, N1, M1, PST 1 2 End stage (D) 1 HCC Portal pressure/ bilirubin Increased 3 nodules 3 cm Associated diseases Normal No Yes Resection Liver transplantation Curative treatments (30%) 5-year survival (40 70%) PEI/RFA TACE Sorafenib Randomized controlled trials (50%) Median survival months Symptomatic treatment (20%) Survival < 3 months Llovet JM, et al. J Natl Cancer Inst. 2008;100:

3 Sorafenib consistently increased overall survival in different patient populations SHARP 1 Asia Pacific Sorafenib (n = 299) Median OS: 10.7 months 1.00 Sorafenib (n = 150) Median OS: 6.5 months Survival probability Placebo (n = 303) Median OS: 7.9 months Survival probability Placebo (n = 76) Median OS: 4.2 months Months Months HR = 0.69 HR = 0.68 HR = hazard ratio; OS = overall survival; SHARP = Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol. 1. Llovet JM, et al. N Engl J Med. 2008;359: Cheng A, et al. Lancet Oncol. 2009;10:25-34.

4 The physician must have two special objects in view with regard to disease, namely, to do good or to do no harm Corpus Hippocraticum Epidemics Bk. I, Sect. 5, trans. Adams

5 Balance between efficacy and toxicity Systemic treatment of advanced HCC has a palliative aim Preserving and possibly improving, patients quality of life should be a primary goal of treatment YES! NO! Efficacy Toxicity Efficacy Toxicity

6 Managing patients with advanced HCC on systemic therapy Di Maio, Roma AISF 2011 Give correct information to patients before starting treatment Adopt preventive measures, when available YES! Careful monitoring during treatment Consider treatment interruption Consider dose reduction Evaluate and discuss risk/benefit ratio Efficacy Toxicity

7 Sorafenib is generally well tolerated Sorafenib is generally well tolerated and the majority of treatment-related AEs are grade 1 or 2 1,2 Common AEs include diarrhea, fatigue, skin rash / desquamation, and HFSR 1,2 These AEs may be managed using supportive measures, 3 which may reduce the need for dose modification WARNING: the majority of safety data from phase 3 trials are in Child Pugh A patients 4 AEs = adverse events; HFSR = hand foot skin reaction. 1. Llovet JM, et al. N Engl J Med. 2008;359: Cheng A-L, et al. Lancet Oncol. 2009;10: Wood LS, Manchen B. Clin J Oncol Nurs. 2007;11: Sorafenib EMEA SmPC. February 2010.

8 Daniele B, Di Maio M. Hot Topics Oncol. 2009;5:19-29.

9 Phase 2 trial: safety of sorafenib by Child Pugh class 1 Di Maio, Roma AISF 2011 Adverse events (%) Child Pugh A (n = 98) Child Pugh B (n = 38) All All serious Fatigue HFSR Diarrhea Bilirubin increase 18 40* Ascites Encephalopathy 2 11 Length of therapy 24.9 weeks 12.9 weeks Dose reductions 31% 21% *Potentially due to worsening cirrhosis 2 or may be related to sorafenib inhibition of UGT1A1 activity Abou-Alfa GK, et al. ASCO 2008; Chicago, IL, USA. 2. Zhu AX, Clark JW. Oncologist. 2009;14:67-9.

10 Sorafenib in patients with Child Pugh B liver dysfunction: GIDEON study Di Maio, Roma AISF 2011 Largest prospective study in unresectable HCC (uhcc) ever conducted, > 400 sites, > 40 countries, 5 designated regions: Asia Pacific, Europe, USA, Latin America, and Japan Eligibility criteria Unresectable HCC Primary endpoint Safety Candidate for systemic therapy Secondary endpoints Efficacy Decision to treat with sorafenib has been made Life expectancy of at least 8 weeks Signed informed consent Source Document Verification Recruitment FPFV: Jan 2009 (n = 3,000) Sorafenib 400 mg b.i.d. Duration of therapy Methods of patient evaluation, diagnosis, follow-up Influence of comorbidities on treatment and outcome Referral patterns First interim analysis: 511 patients enrolled from 140 sites 479 patients were valid for safety analysis Available at: NCT Accessed November Marrero J, et al. AASLD 2010, Boston, MA. Poster: 1721.

11 Treatment-emergent safety data: Child Pugh A and Child Pugh B patients n (%) Child Pugh A (< 7) subgroup n= 278 Child Pugh B (7 9) subgroup n= 134 AEs (all grades) 234 (84) 122 (91) AEs (grade 3/4) 71 (26)/14 (5) 42 (31)/10 (7) Drug-related AEs (all grades) 193 (69) 84 (63) Drug-related Aes (grade 3/4) 58 (21)/ 7(3) 27 (20)/ 4 (3) SAEs (all grades) 93 (33) 80 (60) Drug-related SAEs (all grades) a 28 (10) 22 (16) AEs resulting in permanent discontinuation of sorafenib b 69 (25) 53 (40) Deaths c 49 (18) 50 (37) a An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: death; life-threatening hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; medically important event; b Any AE; c treatment-emergent deaths occurring up to 30 days after last sorafenib dose. Marrero J, et al. AASLD 2010, Boston, MA. Poster 1721.

12 BOOST (B Child HCC patients Optimization Of Sorafenib Treatment) Di Maio, Roma AISF 2011 Patients - HCC advanced - Age >18 - PS Child B Stratification factors: - Child score (7, 8, 9) - CLIP score (1, 2-3, 4-5) - Age(<70, 70+) R A N D O M I Z E A B Best supportiv e care (BSC) Sorafenib 800 mg/d + BSC Primary endpoint: overall survival Sample size: 234 events, 320 patients EUDRACT NUMBER: AIFA code: FARM84SA2X

13 SHARP: drug-related AEs AE* Incidence by grade (%) p value for Sorafenib (n = 297) Placebo (n = 302) between-group comparison Any 3 4 Any 3 4 Any 3 or 4 Overall incidence Diarrhea < < Fatigue < HFSR < 1 0 < < Rash/desquamation Anorexia 14 < < Alopecia < N/A Nausea 11 < Weight loss < Pruritus < Dry skin N/A Pain, abdomen NOS Bleeding < Voice changes < N/A Vomiting Hypertension Dermatology, other < Liver dysfunction < 1 < *Assessed using the NCI-CTCAE (version 3.0) that occurred in at least 5% of patients in either arm. NOS = not otherwise specified. Llovet JM, et al. N Engl J Med. 2008;359:

14 AEs: prevention and management Patients should be informed to take preventive measures, where possible 1 be aware and report AEs as soon as possible 2,3 Patients alerted to possible AEs before beginning treatment may be more accepting of these symptoms 3 are more likely to stay on treatment Porta C, et al. Clin Exp Med. 2007;7: Wood L. Commun Oncol. 2006;3: Robert C, et al. Lancet Oncol. 2005;6: Autier J, et al. Arch Dermatol. 2008;144: Lacouture M, et al. The Oncologist. 2008;13:

15 Sorafenib: dose reductions Starting dose 400 mg (2 x 200 mg) administered orally (po) twice daily (b.i.d) First reduction 400 mg (2 x 200 mg) po every day Second reduction 400 mg (2 x 200 mg) po every two days Llovet JM, et al. N Engl J Med. 2008;359:

16 Hand foot skin reaction HFSR is a group of symptoms affecting the hands and/or feet 1,2 varying degrees of severity that tend to decrease during the course of therapy Common side effect of antiangiogenic therapies that usually occurs during the first few weeks of treatment 3 1. Moldawer N, Wood LS. Kidney Cancer J. 2006;4: Wood LS. Commun Oncol. 2006;3: Alexandrescu DT, et al. Clin Exp Dermatol. 2007;32:71-74.

17 Hand foot skin reaction: grading system* Di Maio, Roma AISF 2011 Grade 1 Clinical characteristics Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema, or discomfort of hands or feet, which does not disrupt patient s normal activities 2 One or more of: painful erythema, swelling, hyperkeratosis of the hands or feet, discomfort affecting the patient s normal activities 3 One or more of: moist desquamation, ulceration, blistering, hyperkeratosis, severe pain of the hands and feet, severe discomfort that causes the patient to be unable to work or perform daily activities *Modified from Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE), published August 9, 2006.

18 Hand foot skin reaction by grade Grade 1 Grade 2 Grade 3 Photos courtesy of Elizabeth Manchen, RN, MS, OCN.

19 Other skin reactions Maculopapular rash Facial rash Body rash Photos courtesy of Elizabeth Manchen, RN, MS, OCN.

20 Di Maio, Roma AISF 2011 HFSR prevention and management: counsel on the 3 C s

21 Di Maio, Roma AISF 2011 HFSR prevention and management: calluses Before sorafenib therapy check condition of hands and feet suggest a manicure/pedicure, when indicated recommend pumice stone for callus or rough spot removal y During sorafenib therapy pressure points items that rub, pinch, or create friction Wood L. Comm Oncol. 2006;3: Robert C, et al. Lancet Oncol. 2005;6:

22 Di Maio, Roma AISF 2011 HFSR prevention and management: creams Apply non-urea based creams liberally Apply urea-based creams sparingly and only to affected areas Avoid products with > 10% urea, as these may increase irritation Avoid systemic steroids Cetaphil Aveeno Udderly Smooth Gold Bond Norwegian Formula Eucerin Alpha-hydroxy acids (AHA) ~ 5% to 8% provide gentle chemical exfoliation apply liberally two times each day Wood L. Comm Oncol. 2006;3: Robert C, et al. Lancet Oncol. 2005;6:

23 Di Maio, Roma AISF 2011 HFSR prevention and management: cushions Protect tender areas Wear well-padded footwear Soak feet in tepid water and epsom salts Use socks/gloves to cover moisturizing creams Use insole cushions or inserts (e.g. silicon, gel) Wood L. Comm Oncol. 2006;3: Robert C, et al. Lancet Oncol. 2005;6:

24 HFSR - suggested managing of sorafenib Timing Dose Grade 1 No change No change Grade 2 1st Interruption until G0 1 No change 2nd Interruption until G0 1 Reduction (1 level) 3rd Interruption until G0 1 Reduction (2 levels) 4th Definitive stop - Grade 3 1st Interruption until G0 1 Reduction (1 level) 2nd Interruption until G0 1 Reduction (2 levels) 3rd Definitive stop - Llovet JM, et al. N Engl J Med. 2008;359:

25 Diarrhea Grade 1 Increase of < 4 stools/day over pretreatment Grade 2 Increase of 4 6 stools/day, or nocturnal stools 39% Grade 3 Increase of 7 stools/day or incontinence; or need for parenteral support for dehydration 8% Llovet JM, et al. N Engl J Med. 2008;359:

26 Diarrhea proposal for dose modification of sorafenib Timing Dose Grade 1 No change No change Grade 2 1st Interruption until G0 1 No change 2nd Interruption until G0 1 Reduction (1 level) 3rd Interruption until G0 1 Reduction (2 levels) 4th Definitive stop - Grade 3 1st Interruption until G0 1 Reduction (1 level) 2nd Interruption until G0 1 Reduction (2 levels) 3rd Definitive stop - Grade 4 Definitive stop -

27 Fatigue Grade 1 Increased fatigue over baseline, but not altering normal activities Grade 2 Moderate (e.g. decrease in Perfomance Status by 1 ECOG level or 20% Karnofsky or Lansky) or causing difficulty perfoming some activities 22% Grade 3 Severe (e.g. decrease in perfomance status by 2 ECOG levels or 40% Karnofsky or Lansky) or loss of ability to perform some activities 3% Llovet JM, et al. N Engl J Med. 2008;359: NCI-CTC version 2

28 Hauser W, et al. Clin Gastroenterol Hepatol. 2004;2:

29 Hypertension Hypertension most frequently occurs early in the course of treatment and is mostly amenable to management with standard antihypertensive therapy Blood pressure should be controlled before starting therapy Monitor blood pressure weekly during the first 6 weeks of therapy and continue thereafter Standard antihypertensives may be used In cases of severe or persistent hypertension that is not responsive to treatment, temporary or permanent discontinuation of sorafenib should be considered Wood L. Comm Oncol. 2006;3: Bhojani N, et al. Eur Urol. 2008;53:

30 Sorafenib in advanced HCC: when to stop? Di Maio, Roma AISF 2011 In the SHARP registrative trial: treatment continued until the occurrence of both radiologic progression (as defined by RECIST) and symptomatic progression (as defined by the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 questionnaire) or the occurrence of either unacceptable adverse events or death Llovet JM, et al. N Engl J Med. 2008;359:

31 Sorafenib in advanced HCC: when to stop? Di Maio, Roma AISF 2011 In clinical practice (in the next single patient!): treatment should be continued as long as the risk/benefit ratio is favorable Efficacy Toxicity

32 A new model of evidence-based medicine Di Maio, Roma AISF 2011 Haynes RB, et al. BMJ. 2002;324:1350.

33 Summary Sorafenib significantly prolonged OS over placebo in advanced HCC Sorafenib therapy is recommended by various guidelines for patients with Child Pugh A or B status; however, caution is required when treating Child Pugh B patients with sorafenib Most AEs related to sorafenib are predictable and manageable Preventive measures can be taken to avoid dose reductions or treatment interruptions Treatment rarely needs to be permanently discontinued Good communication is vital among patients, clinicians, and nurses

34 Thanks for your attention! Bay of Naples from Sorrento