V. Budach – Statements on H&N Cancer - 1

Discussion Panel onPrimary Radiochemotherapy

Volker Budach, MD, PhD Head Department

for Radiation OncologyCharité Campus-Mitte

Berlin

Interdisciplinary Workshop on Modern Treatment Options

Statements on Head and Neck CanerFrankfurt, 27-28 of January 2006

 

V. Budach – Statements on H&N Cancer - 7

Update of the MACH-NC database focusing on concomitant chemo-radiotherapy.

J Bourhis, C Amand, JP Pignon

on behalf of the Meta-Analysis of Chemotherapy in Head and Neck Cancer

(MACH-NC) Collaborative Group

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

V. Budach – Statements on H&N Cancer - 8

Purposes • Confirm the magnitude of the benefit of CT on survival

• Validate the effect in concomitant RT-CT because of uncertainties in the MACH-NC-1* due to heterogeneity between trials

• Increase the statistical power to allow subgroup and subset analyses

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

Bourhis et al., JCO 2005, AbstractBourhis et al., JCO 2005, Abstract

V. Budach – Statements on H&N Cancer - 9

Material & Methods

Eligibility criteria

Trials properly randomizedperformed between 1965 and 2000

RLoco-regional treatment

Loco-regional + chemotherapy

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 10

Material and Methods

Data collection and checking

Updated individual data collected for all randomized patients from published and unpublished trials

Extensive checking & validation to ensure

integrity of rando-mization and follow-up in

collaboration with investigators

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

V. Budach – Statements on H&N Cancer - 11

Intent to treat analysis

Logrank test stratified by

trial

Survival times used to calculate

relative risk (RR)

Absolute benefit calculated from baseline survival

and RR

Material and Methods

Statistical methods

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

V. Budach – Statements on H&N Cancer - 12

24 trials & 5 699 patients

10% in adjuvant 5% in neoadjuvant 85% in concomitant

New randomized trials Included 1994-2000

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 13

87 randomized trials and 16 640 patients

3-arm trials2 x 2 trials

105 comparisons and 17 858 pts

Data analyzedMeta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 14

Chemotherapy timing (n= 17 858)Meta-Analysis of Chemotherapy

in Head & Neck Cancer

MACH-NC

Adjuvant14%

Neoadjuvant32%

Concomitant54%

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 15

Treatment: Chemotherapy No Chemotherapy

PERCENT

0

5

10

15

19

Oral cav. Oroph. Larynx Hypoph. Others

Site of the primary (n= 17 858)Meta-Analysis of Chemotherapy

in Head & Neck Cancer

MACH-NC

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 16

Stage (UICC 1997) (n= 17 858)Meta-Analysis of Chemotherapy

in Head & Neck Cancer

MACH-NC

Treatment: Chemotherapy No Chemotherapy

PERCENT

0

10

20

30

40

Stage I-II Stage III Stage IV

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 17

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC Overall SurvivalAll trials (N=17858 patients)

46962389912881837253633424334615889884315727941104157021662917396758558870

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4 5 6 7 8 9 10Years

ChemotherapyControl

At risk

p<0.0001

Difference : 5 %

36 %

31 %

332307

Median follow-up = 5.7 years

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 22

Overall survival : Concomitant trialsMeta-Analysis of Chemotherapy

in Head & Neck Cancer

MACH-NC

19% + 3%

19% + 3%

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 23

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC Overall SurvivalConcomitant Trials (N=9615 patients)

2843624816779401312171522313180482424630439453174610161359190829524791

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4 5 6 7 8 9 10Years

ChemotherapyControl

At risk

Difference : 8 %

35 %

27 %

p < 0.0001

233186

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 24

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

Difference survival rate

Inclusion Hazard ratio

(95% CI) Chemotherapy

effect (p) Heterogeneity

(p) At 2 years

At 5 years

1965-1993 0,82 (0,76 ; 0,88) <0,0001 <0,0001 7,1 % 6,4 %

1994-2000 0,81 (0,76 ; 0,87) <0,0001 0,27 6,6 % 6,6 %

Total 0,81 (0,77 ; 0,86) <0,0001 0,0001 6,8 % 6,5 %

Overall survival : Concomitant trials (n = 9 615)

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 30

Concomitant trials survival by type of local treatmentMeta-Analysis of Chemotherapy

in Head & Neck Cancer

MACH-NC

21% + 7

17% + 3

27% + 5

1% + 13

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.V. Budach, Statements on H&N Cancer 29

V. Budach – Statements on H&N Cancer - 31

Concomitant trials : effect by type of CTMeta-Analysis of Chemotherapy

in Head & Neck Cancer

MACH-NC

23% + 5

26% + 5

19% + 5

10% + 4

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 33

Concomitant trials: with or without platinMeta-Analysis of Chemotherapy

in Head & Neck Cancer

MACH-NC

23% + 5

20% + 6

26% + 5

11% + 4

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 34

Conclusion

Absolute benefit in concomitant = 8% at 5 years (11% with Cisplatin alone)

Evidence of a higher survival benefit withconcurrent = confirmed

Small benefit of chemotherapy on survival = confirmed (5%)

Benefit of chemotherapy observed in post-op, and with definitive RT (conventional or hyperfractionated)

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 35

Acknowledgments

• Trialists and patients• Association pour la Recherche sur le Cancer • Aventis, Sanofi Synthelabo • Institut Gustave-Roussy • Programme Hospitalier de Recherche Clinique

Meta-Analysis of Chemotherapyin Head & Neck Cancer

MACH-NC

Bourhis et al., JCO 2005, Abstr.Bourhis et al., JCO 2005, Abstr.

V. Budach – Statements on H&N Cancer - 36

Standard Fractionated Radiotherapy ± Concurrent Chemotherapy

W. Budach et al., BMC Cancer 2006, in pressW. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 37

W. Budach et al., BMC Cancer 2006, in pressW. Budach et al., BMC Cancer 2006, in press

Standard Fractionated Radiotherapy ± Concurrent Chemotherapy

V. Budach – Statements on H&N Cancer - 38

Altered Fractionated Radiotherapy ± Concurrent Chemotherapy (same OTT)

W. Budach et al., BMC Cancer 2006, in pressW. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 39

Altered Fractionated Radiotherapy ± Concurrent Chemotherapy (same OTT)

W. Budach et al., BMC Cancer 2006, in pressW. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 40

Altered Fractionated Radiotherapy ± Concurrent Chemotherapy (prolonged OTT)

W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 41

Altered Fractionated Radiotherapy ± Concurrent Chemotherapy (prolonged OTT)

W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 42

Median Survival Impact of Cytostatic Drugs with Concurrent Chemoradiation

W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 45

Chemoradiation vs. Radiotherapy Only studies published after 1992

Reduction of odds ratios

Local control Survival

hyperfract. XRT vs. convent. XRT 0.50 0.60

accelerat. XRT vs. convent. XRT 0.83 0.90*

concurr. CXRT vs. convent. XRT 0.33 0.43

HFX-AF-XRT vs. HFX-AF-XRT + 0.53 0.54

concurr. CHX *= not significant

W. Budach et al., BMC Cancer 2006, in press

V. Budach – Statements on H&N Cancer - 46

Locally Advanced Squamous Cell Carcinomasof the Oro- und Hypopharynx

Concurrent chemoradiation is the standard of

care for inoperable H&N-Cancer !

For patients not amenable for concurrent CXRT,

hyperfractionated XRT is the standard of care!

Conclusions

V. Budach – Statements on H&N Cancer - 47

Perspectives in Head and Neck Cancer

Potential improvement of the Therapeutic Indexby means of:Optimized Radiotherapy Techniques ““IMRT” = IMRT” = IIntensity-ntensity-MModulated odulated RRadioadioTTherapy for dose herapy for dose

escalation and organs at risk/tissue protectionescalation and organs at risk/tissue protection

Small moleculesSmall molecules EGFR-MoAb (Cetuximab, Erbitux, Gefinitib) Cox-II Inhibitors Bevacuzimab

Cytostatic drugs:

Taxanes (Paclitaxel, Doxetaxel), Gemcitabine, Irinotecan

V. Budach – Statements on H&N Cancer - 48

Optimal combination of chemoradiation with standard or altered fractionation?

Do late effects of chemoradiation compromize the therapeutic benefit (therapeutic ratio )?

Can the addition of „small molecules“ additionally improve chemoradiation results?

Is there a definitive role of surgery (for salvage) after chemoradiation?

Open Questions in the Definitive Treatment of Locally Advanced Head and Neck Cancer