Overview of the role of bio-radiation in the management of locally advanced head and neck squamous cell carcinoma.

1. CETUXIMAB IN LA
SCCHN:
HOW FAR WE GO?
MOHAMED ABDULLA M.D.
PROF. OF CLINICAL ONCOLOGY
NEMROCK
CAIRO UNIVERSITY
NEMROCK – 08/02/2015

2. LASCCHN: The Outcome:
Surgery
Radiation
Therapy
Key
Components
 L.R.
 Distant
Metastases
Systemic
Therapy
83%
59%
36%
0%
50%
100%
Localized Regional Metastatic
5-yearSurvival
SEER. Stat fact sheets: oral cavity and pharynx cancer. 2003-2009.

3. MACH-NC: 2009 Update:
93 Trials – 17346 Patients:
J.-P. Pignon et al. / Radiotherapy and Oncology 92 (2009) 4–14

4. MACH-NC: 2009 Update:
93 Trials – 17346 Patients:
J.-P. Pignon et al. / Radiotherapy and Oncology 92 (2009) 4–14

5. MACH-NC: 2009 Update:
93 Trials – 17346 Patients:
J.-P. Pignon et al. / Radiotherapy and Oncology 92 (2009) 4–14

6. MACH-NC: 2009 Update:
93 Trials – 17346 Patients:
J.-P. Pignon et al. / Radiotherapy and Oncology 92 (2009) 4–14

7. MACH-NC: 2009 Update:
93 Trials – 17346 Patients:
J.-P. Pignon et al. / Radiotherapy and Oncology 92 (2009) 4–14

8. MACH-NC: 2009 Update:
93 Trials – 17346 Patients:
J.-P. Pignon et al. / Radiotherapy and Oncology 92 (2009) 4–14
CISPLATIN 100 mg/m2 (D1+22+43) +
RTH

9. Impact of low adherence to treatment of CT on
efficacy

10. LA HNSCC: Theme of
Management:
 RTH  No impact.
 CRT  The most accepted standard, < 70 years.
 Cisplatin: 100 mg/m2 D1+22+43.
 IC  NPX Ca. & Organ Preservation Trial, TPF.
 Sequential:
 Healthy (PS 0 – 1).
 Young.
 N2-3 (Tany).
 T4 not destroying the organ.
 Physician – Patient preference.
www.uptodate.com 09/12/2014
J.-P. Pignon et al. / Radiotherapy and Oncology 92 (2009) 4–14
Can we go better?

11. PI3-K
STAT
AKT
Grb2
SOS RAS
RAF1
MEK
MPA
K
Gene Transcription & Cell Cycle
Progression
1. Angiogenesis
2. Survival
3. Proliferation
4. Progression
Molecular Key Players:
Carter P. Nat Rev. Cancer 2001.
Heinemann V et al. Cancer Treat Rev. 2009.
NK
CELLS

12. Erbitux + RT
Erbitux initial dose (400 mg/m2)
Erbitux (250 mg/m2) + RT (wks 2–8)Stage III and IV
non-metastatic
SCCHN
RT
Bonner JA, et al. N Engl J Med 2006;354:567–578
Curran D, et al. J Clin Oncol 2007;25:2191–2197
R
Primary endpoint: Duration of locoregional control
Secondary endpoints: OS, PFS, RR, QoL, and safety
Bonner Phase III study: Study
Design:
N=424

13. Bonner JA, et al. N Engl J Med 2006;354:567–578
Months
Locoregionalcontrol(%)
100
80
60
40
20
0
0 10 20 30 40 50 60
14.9 months
24.4 months
HR=0.68 [95% CI: 0.52–0.89]
p=0.005
3-year control rate
47%
34%
RT
Erbitux + RT
Bonner Phase III study: Local
Control:

14. Bonner JA, et al. Lancet Oncol 2010;11:21–28
HR=0.73 [95% CI: 0.56–0.95]
p=0.018
0 10 20 30 40 50 60 70
Overallsurvival(%)
5-year survival rate
36%
Months
46%
36%
49.0 months
29.3 months
RT
Erbitux + RT100
80
60
40
20
0
10
30
50
70
90
Bonner Phase III study: 5-Year
Survival:

15. Bonner et al. Lancet Oncol 2010; 11:21-28
Time (months)
Probabilityofsurvival(%)
1.00
0.80
0.60
0.40
0.20
0
0 10 20 30 40 50 60 70
0.10
0.30
0.50
0.70
0.90
Prominent rash group (n=127): Grade 2–4
Mild rash group (n=81): Grade 0/1
51% reduction in the
risk of death (p=0.002)
>68.8
months
p=0.002, HR=0.49 (0.34–0.72)
25.6
months
Cetuximab in LA SCCHN:
Bonner Phase III study: 5-Year Survival & Severity
of Rash:

16. Cetuximab in LA SCCHN:
Change of QoL Over Time:
Curran et al. J Clin Oncol 2007; 25:2191-2197
Globalhealthstatus/QoLscore
100
80
60
40
20
0
Visit
RT
RT + Erbitux
Baseline Week 4 Month 4 Month 8 Month 12
QoL assessment of Bonner study
QoL: Post-baseline scores for the EORTC QLQ-C30

17. *
Listed for its relationship to Erbitux
Bonner JA, et al. N Engl J Med 2006;354:567–578
p<0.001
p=0.01
Patients (%)
0 10 20 30 40 50 60
Mucositis
Dysphagia
Radiation dermatitis
Xerostomia
Fatigue/malaise
Acne-like rash
*Infusion reactions
RT (n=212)
Erbitux + RT (n=208)
90%
10%
COMPLIANCE
Full dose Not Full dose
Cetuximab in LA SCCHN:
Bonner Phase III study: Complications &
Compliance:

18. CRT: Compliance and adherence to treatment:
CRT arms of studies comparing CRT vs RT alone
Cisplatin/5-FU/FA 46%
51%
71%
0 20 40 60 80 100
Carboplatin/5-FU
Cisplatin
Patients receiving all planned doses (%)
10 705030 90
2 cycles at weeks 1 and 5
3 cycles at weeks 1, 4, and 7
3 cycles at weeks 1, 3, and 6
2nd cycle
3rd cycle
3rd cycle
1 Huguenin et al. J Clin Oncol 2004; 22:4665-4673; 2 Calais et al. J Natl Cancer Inst 1999;
91:2081-2086;
3Wendt et al. J Clin Oncol 1998; 16:1318-1324
1
2
3

19. CRT versus Bio-Radiotherapy:
TREMPLIN Study: Safety Data:
• RT: 70 Gy
• Erbitux: initial dose 400 mg/m2 prior to RT
then 250 mg/m2 weekly for 7 weeks
• Cisplatin: 100 mg/m2 on days 1, 22 and 43
1. Lefebvre JL et al. J Clin Oncol 2009. 2. Lefebvre JL et al. J Clin Oncol 2011.

20. CRT versus Bio-Radiotherapy:
Projected Efficacy:
2) Bonner J.A, et al. ASTRO 2008
1) Pignon JP, et al. Lancet 2000;355:949–955
Prominent rash group *
Most of the randomised trials have used
a dose of cisplatin of 100 mg/m2, three
times throughout the course of
radiotherapy (cumulative dose of 300
mg/m2).

21. CRT versus Bio-Radiotherapy:
Survival Advantages:
Huguenin, Karl 2004
two cycles of concomitant
cisplatin (20 mg/m2 on 5
days of weeks 1 and 5).
P= NS

22. CRT versus Bio-Chemo-
Radiotherapy:
CRT
Bio-Radiotherapy
Bio-Chemo-Radiotherapy

23. RTOG 0522: Progression-Free
Survival and Overall Survival
Pts at Risk, n
448 316 217 78
447 302 197 80
Pts at Risk, n
448 385 266 96
447 378 251 94
Ang KK, et al. ASCO 2011. Abstract 5500.
PFS(%)
0
25
50
75
100
Yrs After Randomization
0 1 2 3
HR: 1.05 (95% CI: 0.84-1.29;
log-rank, 1-sided P = .66)
2-Yr Rate, % (95% CI)
64.3 (59.7-68.8)Cisplatin
63.4 (58.7-68.0)Cisplatin + cet
Primary Endpoint
OS(%)
0
25
50
75
100
Yrs After Randomization
0 1 2 3
HR: 0.87 (95% CI: 0.66-1.15;
log-rank, 1-sided P = .17)
2-Yr Rate, % (95% CI)
79.7 (75.9-83.6)Cisplatin
82.6 (78.9-86.3)Cisplatin + cet

24. Radiation Therapy Oncology Group
RTOG-0234:
Stage III/IV
SCCHN High
Risk
Surgery
Cetuximab +
Cisplatin 30 mg/m2
+ RTH 60 Gy
Cetuximab +
Docetaxel 15
mg/m2
+ RTH 60 Gy
J Clin Oncol 32:2486-2495. © 2014 by American Society of Clinical Oncology
DFS OAS
57%
66%
69%
79%

27. This is where all footnotes and references go.

28. • At present, induction chemotherapy is not
considered standard treatment in advanced disease.
• ICT followed by RT-CT (so-called sequential CT-RT) is
still under evaluation.
• The overall toxicity of this approach can be
substantial thus compromising the final result.
•Radiotherapy given concomitantly with cetuximab has
demonstrated a higher response rate, longer disease-
free progression and longer overall survival versus
radiotherapy alone [II, B].
•The magnitude in effect was similar or even better than
that achieved by concomitant chemoradiation, it proved
to be less toxic

29. Take Home Message:
 Cetuximab is an approved key component
plus radiation therapy of LA HNSCC.
 Significant lower toxicity profile than platinum
based CRT  more adherence to treatment
schedule.
 Cisplatin + RTH: 300 mg/m2.
 Cetuximab + Docetaxel + RTH = Ideal
Partners.
 Cetuximab + RTH = Level 1 Evidence in
Guidelines.

30. Thank You