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:
g.daniele@istitutotumori.na.it
• 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