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Méta-analyses - PPT Presentation

de chimiothérapie dans les cancers des VADS actualisation JeanPierre Pignon Pierre Blanchard Anne Lee Laureen Majed Sophie Marguet Claire Petit Cécile Landais ID: 573113

induction concomitant meta lrt concomitant induction lrt meta analysis crt trials results patients network adjuvant chemotherapy clrt taxpf treatment standard npc trial

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Slide1

Méta-analyses

de chimiothérapie dans les cancers des VADS: actualisation

Jean-Pierre Pignon, Pierre Blanchard, Anne Lee, Laureen Majed, Sophie Marguet, Claire Petit, Cécile Landais, Julie Leclercq, Béranger Luéza, Federico Rotolo,Benjamin Lacas, François Janot, Jean Bourhis,Service de biostatistique, dpts de radiothérapie et chirurgie cervicofaciale,Plateforme LNCC Méta-analyse en Oncologie, INSERM U1018 CESP, Hong-Kong NPC Collaborative Group, CHU vaudois de Lausanne. Slide2

Head and neck

meta

-analyses Meta-analysis

Initial(no. trials, pts)

Publication

Update 1

(no. trials, pts)

Publication

Update 2

(no. trials, pts)

Publication

MACH-NC

(CT, HNSCC)1965-1993*,$(63,10 741)Lancet 20001994-2000$(87, 16 485)Rad Oncol 2009/20112001-2010£,**,$$(102, 19 325)ESMO 2016MAC-NPC(CT, NPC)< 2002(8, 1 753)Red 20062002-2010£,$$(19, 4 806)Lancet Oncol 2015 Initiated in 2016MARCH(RT, HNSCC)1970-1998(15, 6 515)Lancet 20061999-2011£,%(30, 11 140)ECCO 2013ESTRO 2014Final analysis 2015 and manuscript 2016

* MA on larynx preservation  ; $ MA sequential vs. concomitant£ Effect at 10 years, data on toxicity and compliance ; % Postoperative trials eligible, MA standard radiotherapy (RT) + CT vs. modified fractionation RT ** JCO 2013 TPF vs. PF; $$ Trials of Timing 1 ± Timing 2 eligible

2Slide3

Meta-analysis of chemotherapy in

nasopharynx

carcinomaStandard MA (Blanchard et al. Lancet Oncol 2015)Network MA (Ribassin-Majed et al. JCO 2016)Surrogate analysis (Rotolo et al. JNCI 2016)

3Slide4

MAC-NPC :

Material

for network and standard MA20 trials, 5 144 patients26 comparisonsmedian follow-up = 7,4 years

Accrual < 2011

MA standard: 4 groups1. RT vs. induction CT (

IC) + RT CRT vs.

IC-CRT2. RT vs. adjuvant CT (

AC) + RT CRT + CRT-

AC3. RT vs. concomitant CT (C) + RT

IC-RT vs. IC-CRT

4. RT vs. CRT-AC

4Slide5

Standard meta-analysis: summary results

 

Overall SurvivalProgression-Free Survival

Loco-regional Control

Induction

*

 0.96 [0.80;1.16]

0.81 [0.69;0.95]

0.84 [0.66;1.07]

Adjuvant

*

 0.87 [0.68;1.12]

0.80 [0.64;1.00]0.61 [0.41;0.93]Concomitant*0.80 [0.70;0.93]0.81 [0.71;0.92]0.82 [0.67;1.01]Concomitant and adjuvant* 0.65 [0.56;0.76]0.62 [0.53;0.72]0.54 [0.41;0.71]Overall* 0.79 [0.73;0.86]0.75 [0.69;0.81]0.73 [0.64;0.83]Overall test**<0.0001 <0.0001<0.0001Interaction test (between timing and treatment effect)

** 0.010.040.05

Residual heterogeneity test

**

0.36 

0.62

0.78

*

Hazard ratio [95% confidence interval];

**

p-value;

***

toxicity related to one trial, disappears after exclusion of this trial (new HR: 0.91 [0.39;2.15])

*

Hazard

ratio [95% confidence interval

]

** p-value

5Slide6

Standard meta-analysis of CT for non metastatic NPC: ConclusionsOverall benefit of the addition of

chemotherapy on OS (~6% at 5-years), PFS, locoregional and distant control, and cancer deathSuperiority of concomitant

(~9-12% at 5-years) over induction or adjuvantComparison between concomitant +/- adjuvant (or induction) deserves further studies6Slide7

Individual data to compute hazard ratio from log-rank test, stratified by trial Frequentist approach with

random effect model in case of heterogeneityOverall survival (OS) main endpoint

Heterogeneity and inconsistency were assessed by a global Cochran Q statistic. P-score (P-s) used to rank treatments = percent of certainty to be the best treatmentNetwork meta-analysis : Methods

7Slide8

Second

F

irst

Conc

-CT-RT (CRT)

Induction CT-RT (IC-RT)

IC-CRT

CRT-AC

IC-CRT-ACRT-Adjuvant CT

(AC-RT)Radiotherapy (RT)

8Slide9

Network meta-analysis in patients with non metastatic NPC: conclusion

9

The

addition

of

adjuvant chemotherapy

(CT) to concomitant CT-radiotherapy (CRT) achieved the highest survival benefit and consistent improvement for all endpointsThe addition of

induction chemotherapy to CRT achieved the highest effect on distant controlRegimens with more CT were associated with increased risk of acute

toxicityResults of recent trials on induction CT will clarify the role of the timing of CT Slide10

MAC-NPC:

surrogate analysis

(Rotolo et al JNCI 2016)PFS and DMFS* are valid surrogate endpoints for OS in randomized CT trials of

patients with LANPC PFS can be observed earlier than DMFS and showed more robust results

Statistical methods

Individual level: rank correlation ρ between surrogate and OS estimated from the bivariate distribution

Trial level: coefficient of determination R2 between treatment

effects (log hazard ratios) on surrogate and OS, estimated from a linear regressionResults and conclusion

*DMFS = Distant Metastasis

-Free Survival

10Slide11

Meta-analysis of chemotherapy in head en neck cancer

Preliminary results:

Standard

MA (Blanchard et al. ESMO 2016)

Network MA (Petit et al. ECCO 2017)

11Slide12

Locoregional treatment (LRT ) vs. LRT + CT: Overall Survival

Trials on concomitant CT

20 092 patients and 13 904 deaths (69%)Median follow-up: 6.7 yearsAccrual between 1965 and 2010

12Slide13

Overall

Survival

Progression-Free

Survival

LRT vs LRT + CT

0.89 [0.86;0.92]

0.87 [0.84;0.90]

Concomitant CT

0.83 [0.79;0.87]

0.80 [0.76;0.83]

Induction CT

0.97 [0.91;1.03]0.98 [0.92;1.04]Adjuvant CT1.02 [0.92;1.13]0.99 [0.89;1.10]Interactionp<0.0001p < 0.0001Induction (+/- adj.) vs concomitant CT-RT = direct comparison (8 trial, 1 214 patients)

0.84 [0.74;0.95]

0.85[0.75;0.96]

Summary for overall and progression-free survival

Indirect

comparison

13Slide14

No change: concomitant CT > induction

and adjuvant CT; superiority of platin alone, and 5FU plus

platin (PF) compared to the other concomitant chemotherapyOlder (>70) and frail (PS >2) patients might not benefit (or benefit less) from CTFor induction chemotherapy, PF is superior to the absence of CTNo conclusion for TPF as results are heterogeneous (some trial with major toxicity and data collection still ongoing)Second update of the MACH-NC data base : additional trials and

long term follow-up : conclusion

14Slide15

CONFIDENTIAL

117 trials, corresponding to 150 comparisons from MACH-NC and MARCH (comparison of modified fractionation and standard RT)28 804 patients

16 modalities of treatment35 direct comparisons19 131 deaths and 20 586 events for PFS15

Network

meta-analysis

:

ECCO 2017Slide16

Label

Description

LRT Standard RT +/- surgery CLRTP LRT + concomitant CT with platinCLRTnoP LRT + concomitant CT without platin

ICother - LRT Induction CT

other + LRTICPF

- LRT Induction CT PF

+ LRTICTaxPF - LRT

Induction CT TaxPF + LRT

LRT - AC LRT + adjuvant CT

ICother - CLRT

Induction CT

other

+ LRT+ concomitant CTICPF - CLRT Induction CT PF + LRT + concomitant CTICTaxPF - CLRT Induction CT Tax-PF + LRT + concomitant CTHFRTHyperfractionnated RTMARTModerately accelerated RTVARTVery accelerated RTHFCRT Hyperfractionnated RT + concomitant CTACRT Accelerated (moderately and very) RT + concomitant CTCLRTnoP - AC CLRT without platin + adjuvant CTCLRTPICTaxPF-CLRTCLRTnoPCLRTnoP-ACICother-LRTICPF-LRTICTaxPF-LRTICother-CLRTICPF-CLRT16

Network for OSCONFIDENTIALSlide17

CONFIDENTIAL

Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the

best treatment in all analyses. The hazard ratios (HR) of HFCRT compared to platinum-based CRT was 0.80 [95% CI 0.65-0.99] for OS (P-s 0.97) and 0.77 [95% CI: 0.62-0.96] for progression-free survival (P-s 0.98). The superiority of HFCRT was robust to sensitivity analysesThree other modalities of treatment had a better P-score than platinum-based CRT (P-s 0.78) but their HR for death were not significantly different: induction chemotherapy (TaxPF) followed by LRT (IC-LRT, (P-s 0.89)), accelerated radiotherapy with concomitant chemotherapy (ACRT, (P-s 0.82)) and induction chemotherapy (TaxPF) followed by CRT (IC-CRT, (P-s 0.79))Network meta-analysis in patients with non metastatic HNSCC: Results

17Slide18

CONFIDENTIAL

Treatment comparison

RankNetwork meta-analysisNumber of trials per comparisonHR

95% CI

Compared to platinum-based CRT

 

Hyp

Frac (HF) Conc CT-RT (CRT)

1

0.80

[0.65-0.99]

2Ind CT (IC) (TaxPF) followed by LRT20.90[0.73-1.12]0Acc CRT30.97[0.86-1.10]4IC (TaxPF) followed by CRT40.98[0.80-1.21]3Compared to LRT HFCRT10.62[0.51-0.76]2IC (TaxPF) followed by LRT20.70[0.57-0.86]1ACRT30.75[0.67-0.85]1IC (TaxPF) followed by CRT40.76[0.62-0.94]0Platinum-based CRT50.77[0.72-0.83]23

18Network meta-analysis in patients with non metastatic HNSCC: ResultsSlide19

CONFIDENTIAL

The results suggest the superiority of HFCRT

for the treatment of LAHNC Although toxicity is not addressed, these results, which ideally need to be confirmed by RCTs, could be clinically useful in advanced diseases with a high risk of locoregional failure, as represented by the patients in these meta-analysesNetwork meta-analysis is a new method and results based on this method should be interpreted with caution (potential bias, robustness of the results) and the uncertainty of ranking be taken into accountNetwork meta-analysis in patients with non metastatic HNSCC : conclusion

19Slide20

Les membres des groupes coopérateurs MACH-NC, MARCH et MAC-NPC et leur patients sans qui ce travail n’aurait pas été possibleLes membres du service de Biostatistique

et d’Epidémiologie de Gustave Roussy, en particulier Françoise Delassus et le reste de l’équipe méta-analyseL’INCa

, la Ligue, l’ARC et Sanofi pour leur soutient financier sur le long terme Remerciements 20Slide21

Gustave Roussy: Meta-analysis team

21