Approccio Metodologico alla terapia dell`HCC
Transcription
Approccio Metodologico alla terapia dell`HCC
Approccio Metodologico alla terapia dell’HCC Gennaro Daniele Oncologo Medico S.C. Sperimentazioni Cliniche Istituto Tumori G. Pascale Napoli Grazie • Andrea Casadei Gardini e Stefano Tamberi • Valentina Rivaroli • Prof. Bolondi • Voi ché non mi lincerete… The evidence J Llovet World GI 2015 Linee Guida AIOM 2015 7% 2% 1++ 15% 26% 4% 1+ 1- • RCT vs nonRCT 2++ 2+ 9% 17% 20% 23 4 • Evidenza estrapolata • Elogio della randomizzazione • Quando la randomizzazione non è tutto: • Le giuste conclusioni ai giusti pazienti… • A confronto con i confronti impropri How to compare? • This is a typical example of an unfair comparison… • Patients do not have the same a priori possibility to benefit from a treatment (whethever) • Moreover since the choice was “one-sided” the bias (systematic) was monolaterally in favour of the “experimental” Advantages of Randomized Control Clinical Trial 1. Randomization "tends" to produce comparable groups Design Randomized Concurrent (Non-randomized) Historical (Non-randomized) Sources of Imbalance Chance Chance & Selection Bias Chance, Selection Bias, & Time Bias 2. Randomization produces valid statistical tests Reference: Byar et al (1976) NEJM 542-03-#10 Disadvantages of Randomized Control Clinical Trial 1. Generalizable Results? – Subjects may not represent general patient population – volunteer effect 2. Recruitment – Twice as many new patients 3. Acceptability of Randomization Process – Some physicians will refuse – Some patients will refuse 4. Administrative Complexity 542-03-#11 Bias of Non-RCT’s • Example - Peto (1979) Biomedicine Trials of anticoagulant therapy Design Effect 18 Historical #Patients 900 P<0.05 Observed 15/18 50% 8 Concurrent 3000 5/8 50% 6 Randomized 3000 1/6 20% • Biases – False positives – Magnitude of effect 542-03-#12 Ethics of Randomization (1) • Statistician/clinical trialist must sell benefits of randomization • Ethics Þ MD should do what he thinks is best for his patient – Two MD's might ethically treat same patient quite differently • Chalmers & Shaw (1970) Annals New York Academy of Science 1. 2. 3. If MD "knows" best treatment, should not participate in trial If in doubt, randomization gives each patient equal chance to receive one of therapies (i.e. best) More ethical way of practicing medicine 542-03-#13 Ethics of Randomization (2) • Byar et al. (1976) NEJM 1. RCT Þ honest admission best is not known! 2. RCT is best method to find out! 3. Reduces risk of being on inferior treatment 4. Reduces risk for future patients 542-03-#14 Comparing Treatments • Fundamental principle • Groups must be alike in all important aspects and only differ in the treatment each group receives • In practical terms, “comparable treatment groups” means “alike on the average” • Randomization • Each patient has the same chance of receiving any of the treatments under study • Allocation of treatments to participants is carried out using a chance mechanism so that neither the patient nor the physician know in advance which therapy will be assigned • Blinding • Avoidance of psychological influence • Fair evaluation of outcomes 542-03-#15 Clearly… Randomisation is not Panacaea(1) Sorafenib improves overall survival in patients with advanced HCC SHARP SHARP Median, sorafenib Median, placebo Hazard Ratio (95% CI) 10.7 months 7.9 months 0.69 (0.55 – 0.87) Llovet et al. N Engl J Med 2008; 359:378-390 Llovet et al. N Engl J Med 2008; 359:378-390 First step: Internal validity • Was the trial well-conducted, to minimize bias? • Can we trust in the observed results? Internal validity • Internal validity is threatened by bias, “any process at any stage of inference tending to produce results that differ systematically from the true values.” • Internal validity implies that the differences observed between groups of patients allocated to different interventions may, apart from random error, be attributed to the treatment under investigation. Second step: External validity • May we apply the observed results to the patients we have to treat in the real world? From real world to clinical trial… Ill Go to hospital N Trial available Trial offered Trial eligible Randomized From clinical trial to real world… Ill Go to hospital Generalize to ill patients, present and future Inference N Trial available Trial offered Trial eligible Randomized From clinical trial to real world… Ill Go to hospital Generalize to ill patients, present and future Inference =? N Trial available Trial offered Trial eligible Randomized Two diseases in one: HCC and underlying liver disease • Impact on prognosis • Impact on tolerability • Impact on risk / benefit ratio of treatments GK Abou Alfa, Systemic therapeutic issues in HCC, ASCO 2004 Bologna, 04 Novembre 2011 Daniele B, Di Maio M. Hot Topics in Oncology 2009; 5: 19-29 Llovet JM et al, J Natl Cancer Inst 2008; 100: 698-711. Llovet JM et al, J Natl Cancer Inst 2008; 100: 698-711. Sorafenib in HCC: Practice HCC Stage 0 PST 0, Child-Pugh A Stage A–C PST 0–2, Child-Pugh A–B 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 Stage D PST > 2, Child-Pugh C Advanced stage (C) Portal invasion, N1, M1, PST 1–2 End stage (D) 3 nodules ≤ 3 cm 1 HCC Portal pressure/ bilirubin Associated diseases Increased Normal Resection No Liver transplantation Curative treatments Yes PEI/RFA TACE Sorafenib Randomized controlled trials Symptomatic treatment Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711. Bologna, 04 Novembre 2011 A conflict… “Methodological purism” Physicians strictly consider the external validity of trial results, denying sorafenib to Child B patients Treatment of Child B patients remains unmet need No therapeutic chance is offered to these patients Di Maio M et al, Nature Reviews Clinical Oncology 2009; 6: 505-6 “Methodological purism” Physicians strictly consider the external validity of trial results, denying sorafenib to Child B patients Treatment of Child B patients remains unmet need No therapeutic chance is offered to these patients “Clinical pragmatism” Physicians consider the absence of therapeutic altrernatives and offer sorafenib to Child B patients Caution in monitoring adverse effects A conflict… Di Maio M et al, Nature Reviews Clinical Oncology 2009; 6: 505-6 The solutions… The non-interventional GIDEON study Prospective study in unresectable HCC, 3329 patients in 39 countries, 5 designated regions: Asia–Pacific, Europe, USA, Latin America, and Japan Eligibility criteria • Unresectable HCC • Candidate for systemic therapy • Decision to treat with sorafenib has been made • Life expectancy of at least 8 weeks • Signed informed consent • Source Document Verification Primary endpoint • Safety Recruitment FPFV: Jan 2009 (n = 3,000) Sorafenib 400 mg b.i.d. Secondary endpoints • Efficacy • Duration of therapy • Methods of patient evaluation, diagnosis, follow-up • Influence of comorbidities on treatment and outcome • Referral patterns Second interim analysis (> 1500 patients) Lencioni R, et al. Int J Clin Pract. 2014 May;68(5):609-17. GIDEON-Preliminary Overall Survival by Child-Pugh Status* at Study Entry Child-Pugh A (<7) (n=984), median (95% CI) 312 (284, 341) days 10.3 months Child-Pugh B (7-9) (n=376), median (95% CI) 147 (126, 189) days 4.8 months Child-Pugh C (>9) (n=36), median (95% CI) 62 (46, 94) days 2.0 months 1,0 Survival distribution function 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0 100 200 300 400 Time since start of treatment (days) * 207 patients not evaluable. CI=confidence interval. Adapted from Marrero JA et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 500 600 …The benefit of sorafenib in patients with more advanced liver disease could not be evaluated from sub-group analysis since both of the pivotal studies required well preserved (Child-Pugh A) liver function as an eligibility criteria. However, subsequent field of practice studies have included patients with more advanced liver disease and, for patients with Child Pugh B disease, survival ranges from 2.0-7.7 months suggesting that the benefit may not be clinically meaningful…. Unfortunately, the open-label experience in the GIDEON study of more than 3,000 patients, many of whom will have CPB cirrhosis, will provide very little useful information without a matched untreated control group. Oncology (Williston Park). 2011 Mar;25(3):296, 298, 300. Bruix J et al, J Hepatol 2012 Jun 19. [Epub ahead of print] N Engl J Med 2006, 354: 1667 ISIS-2 trial: Aspirin vs Placebo Mortality 1 month after myocardial infarction All cases N. of deaths A vs P P 804 vs 1016 <0.0001 ISIS-2 trial: Aspirin vs Placebo Mortality 1 month after myocardial infarction Zodiac sign N. of deaths A vs P P All cases 804 vs 1016 <0.0001 Other signs 564 vs 869 <0.0001 Libra or Gemini 150 vs 147 0.5 (ns) “…The efforts and resources being invested in the GIDEON study would be better spent in performing a well-designed placebo-controlled trial in CPB patients…” Oncology (Williston Park). 2011 Mar;25(3):296, 298, 300. Bologna, 04 Novembre 2011 BOOST (B Child HCC patients – Optimization Of Sorafenib Treatment) Best Supportive Care (BSC) Patients: •HCC Avanzato • ≥18 anni •PS 0-2 •Child-Pugh B Stratification factors: - Child score (7, 8, 9) - CLIP score (1, 2- 3, 4-5) - Age(<70, 70+) Sorafenib 400 mg b.i.d. + BSC P.I.: Dr Bruno Daniele Coordinatore: Dr Francesco Perrone Statistico:Prof Ciro Gallo Endpoint primario: overall survival (OS) Bologna, 04 Novembre 2011 BOOST Disegno dello Studio • Multicentrico • Lo studio è dimensionato per verificare se l’aggiunta di sorafenib alla BSC in questi pazienti produce un vantaggio uguale a quello dello studio SHARP (HR: 0.70) • Potenza dell’80% e alfa bilaterale 0.05: 234 eventi complessivi per 320 pazienti complessivi. • Ipotizzando un arruolamento di 20 pazienti al mese si può prevedere la chiusura dello studio entro 2 anni dall’arruolamento del primo. Bologna, 04 Novembre 2011 BOOST è aperto • 22 pazienti arruolati finora • Per informazioni chiedete a me: [email protected] • O aderite su: www.usc-intnapoli.net Bologna, 04 Novembre 2011 Randomisation is not Panacaea(2) Mi avvio verso le conclusioni.. …nel 2016: Take home message Approccio Metodologico: • C’è ancora tanta strada da fare… • Ce la faremo (c’è bisogno di un cambiamento radicale)? Conclusion • • • • GMH aka “Amazing Grace” Died asleep at 86 She invented the term “bug” “The most important thing I've accomplished, other than building the compiler, is training young people. They come to me, you know, and say, 'Do you think we can do this?' I say, "Try it." And I back 'em up. They need that. I keep track of them as they get older and I stir 'em up at intervals so they don't forget to take chances” “La frase più pericolosa in assoluto è: abbiamo sempre fatto così” Grace Mary Hopper