1. The International Federation
of Head and Neck Oncologic Societies
Current Concepts in Head and Neck Surgery and Oncology 2012
Larynx Preservation: the
Nonsurgical Approach
Jan B. Vermorken

2. Outline
• Considerations in decision making
• Milestones in larynx preservation
• Role of radiotherapy
• The importance of timing chemotherapy
• First generation larynx preservation trials
• Second generation larynx preservation trials
• The design of future trials
2012 • Conclusions

3. New Findings in Recent Years
• HPV is a risk factor for cancer of the
oropharynx
• Therapeutic agents against molecular
targets (EGFR)
• Expanded role of chemotherapy (IC,
CCRT)
• Improved irradiation techniques (IMRT)
• New imaging techniques (PET)
2012
• Survivorship issues
Haddad RI, Shin DM N Engl J Med 2008; 359: 1143-54

4. Biologist
HN Surgeon Pathologist Radiation
Oncologist
Anesthesiologist
Medical Internist
Oncologist GP
Patient
Dietician Speech
Therapist
Radiologist Social worker
Psychologist
Guidelines Clinical trials
2012

5. Considerations in Decision Making
• Define risk group (TNM, UICC, AJCC)
• Pretreatment considerations1
– Comorbid chronic disease (pulmonary, CV,
digest.)
– Malnutrition (severe in > 25% of patients)
– Oral health (periodontal disease, infections,
caries)
• Morbidity of treatment (radiotherapy,
chemotherapy, targeted therapy, surgery)1
• What do patients want? (cure, long living,
no pain)2
2012
1Schantz SP et al. Cancer: Principles & Practice of Oncology, 6th ed. 2001; 797-860
2List, Head and Neck, 2004

6. ESMO Clinical Practice Guidelines 2010
Locoregionally Advanced Disease
Level of Grade of
evidence recommendation
Surgery → RT or CCRT I A
Concomitant CT and I A
RT*
Cetuximab plus RT II B
ICT → RT for organ II A
preservation
CCRT for organ II A
preservation
2012
*in case of mutilating surgery and in nonresectable disease
Gregoire V et al, Ann Oncol 2010: 21 (suppl 5): VI84-VI86

7. Milestones in Larynx Preservation
Courtesy of Prof. J-L Lefebvre
Randomized trials
on larynx preservation
1st. TL 1st. RT
VA EORTC RTOG GORTEC EORTC Tremplin
1st. PLs
1873 1878 1903 1970s 1994 1996 2003 2005 2007 2009
partial
radiotherapy laser ASCO biotherapy TORS
surgery
2012 CTscan 1982
MRI
chemotherapy

8. Radical (Mutilating?) Surgery in LC and HPC
Total laryngectomy (± partial pharyngectomy),
Centre Oscar Lambret (1974 - 1983): 5-yr results
site: # control survival
> clavicles
larynx * 254 88 % 48 %
hypopharynx ** 244 84 % 35 %
NB: postop RT * 40 %. ** 100%
2012

9. Alternative to Mutilating Surgery
• Non-Mutilating Surgery
- endoscopic laser CO² surgery
- extended partial surgery
• Non-Surgical Treatment
- definitive radiation therapy
- chemotherapy-based protocols
2012

10. Altered vs Standard Fractionation
Meta-Analysis
Regimens Absolute benefit Risk p
at 5 years reduction
Local-regional Control
Hyperfractionation 9.4 % 24 % <0.0001
AFX (≅ Total Dose) 7.3 % 21 % <0.0001
(â Total Dose) 2.3 % 10 % NS
Survival
All group 3.4 % 8% 0.003
2012
Bourhis (Pignon), Lancet 368:843, 2006

11. Meta-Analysis : Trials on
Altered Fractionation
Survival by Site
No. Deaths / No. Entered
Category Alt. fractionated RT Control O-E Variance Hazard Ratio Interaction test
Site
Oral cavity 282/370 278/346 -15.7 134.9
p = 0.20
Oropharynx 1150/1673 1127/1576 -53.9 561.2
Larynx 586/1231 553/1142 -19.9 276.8
Hypopharynx 235/297 227/282 -12.3 110.7
Others 52/69 45/72 8.9 19.6
0.0 0.5 1.0 1.5 2.0
Alt. fractionated RT better | Control better
2012
Bourhis J et al. Lancet 2006

12. Alternative to Mutilating Surgery
• non mutilating surgery
- endoscopic laser CO² surgery
- extended partial surgery
• non surgical treatment
- definitive radiation therapy
- chemotherapy-based protocols
2012

13. Rationale for 1st Generation LP Trials
• High response rates with induction
chemotherapy
– Response > 90%, complete resp.> 60%
(Decker et al, Cancer 1983)
• Chemotherapy may predict
radiosensitivity
– 42/60 CR/PR → after RT, CRR 97%
2012 – 18/60 NC/PD → after RT, CRR 6%
(Ensley et al, Cancer 1984)

14. Neoadjuvant Chemotherapy in Resectable SCCHN
1st generation
Study Tumor Size Treatment No. of Survival LP
Group and stage arms pts (at 2 or 5 yrs)
VA Larynx TL + RND + RT 332 60% (2)
T1-T4, N2-3 CT → RT* 68% (2) 64%
EORTC Hypopharynx TL + RND + RT 202 35% (5)
T2-T4, N0-2b CT → RT* 30% (5) 57%
2012
* non-responders → S + RT

15. 100
90
Duration of Survival
80
70 Hazard Ratio: 0.88 (95% CI: 0.65 - 1.19)
60 P-value for non-inferiority of LP: P=0.0015
50
40
30 Larynx preservation
20 Surgery
10
0 (years)
0 2 4 6 8 10 12 14 16
O N Number of patients at risk : Treatment
81 94 49 36 26 14 9 5 3 Surgery
83 100 62 47 27 17 8 4 1 LP
2012

16. Randomized Trials of ICT in LA-HNC
Revisited
Trial Arms Outcome
CA 139-322 (2005) PF vs PPF CCR (TTP, OS*)
Resectable/nonresectable CRT (CDDP) Improved with PPF
EORTC 24971/TAX 323 PF vs TPF PFS (RR, OS)°
Nonresectable (2007) RT Improved with TPF
TAX 324 (2007) PF vs TPF OS (PFS, RR)°
Resectable/nonresectable CRT (Cb) Improved with TPF
GORTEC 2000-01 PF vs TPF LP (OS, DFS)+
2012
Resectable (2009) T(P)L vs RT Improved with TPF
*significant only in unresectable disease (JCO); °(Vermorken, Posner) NEJM; + (Pointreau) JNCI

17. GORTEC Phase III Larynx Preservation Trial
Comparing TPF and PF Induction Therapy
for Hypopharynx and Larynx Cancer
2012
At 3 years: LP 70.3% with TPF, 57.5% with PF (p=0.03)
Pointreau Y, et al. J Natl Cancer Inst 2009; 101: 498-506

18. Radiation + Chemotherapy vs
Radiotherapy Alone
Meta-analysis
Absolute benefit Risk p
Regimens at 5 years reduction
Adjuvant 1% 2 % NS
Neoadjuvant 2% 5 % NS
- NACT with PF 5% 12 % 0.01
Concurrent 8% 19 % < 0.0001
2012
Pignon et al, Lancet 335:949, 2000 (Pooled data from trials performed between 1965 and 1993)
Monnerat et al, Ann Oncol 2002; 13: 995-1006

19. Neoadjuvant Chemotherapy in
Resectable SCCHN
2nd generation LP trials
Study Tumor size Treatment No. of 5-year
Group and stage arms pts survival
Glottic & supragl. PF → RT 173 59.2%
RTOG
N0-1, N2, N3 CRT (CDDP) 172 54.6%
91-11A
T2, T3+, T3-, T4 RT 173 53.5%
EORTC Larynx & Hypophar PF x 2-4 → RT 224 48.5%
24954B T2-T4, N0-N2 PF alt. RT 286 51.9%
2012
+with fixed cord involvement; -without cord fixation
Aforastiere A et al, ASCO 2006; Blefebvre JL et al, JNCI 2009

20. Larynx preservation rates according to treatment group
2012
Forastiere et al, 2003

21. RTOG 91-11:Phase III Trial of Larynx
Preservation:
ASCO- 5-Year Update #5517
PF CRT XRT
LFS 44.6% 46.6% 33.9% p < .011
LRC 54.9%* 68.8%* 51% p < .0018
DM 14.3% 13.2% 22.3%
DFS 38.6%* 39% 27.3%* p < .0016
Survival 59.2% 54.6% 53.5%
1. PF was Equivalent to CRT for LFS
2. CRT had Better LRC Than PF
3. DFS Was Identical But Overall Survival Favored PF
2012 4. Did Patients Fare Better With PF Because They Had
Subtle Improvements in Function

22. RTOG 91-11
Phase III Trial of Larynx Preservation
Laryngectomy-Free
Overall Survival
Survival
2012
LFS=laryngectomy-free survival Forastiere. ASCO. 2006

23. RTOG 91-11: Cause of Death
Induction Concomitant RT Alone
n=89 n=106 n=96
# (%) # (%) # (%)
Larynx cancer 41 (46) 37 (35) 56 (58)
Second primary 11 (12) 17 (16) 12 (13)
Complication of 8 (9) 10 (9) 5 (5)
protocol treatment
Complication of other 2 (2) 2 (2) 0 (0)
treatment
Unrelated to cancer 18 (20) 36 (34) 18 (19)
or treatment
2012
Unknown 9 (10) 4 (4) 5 (5)

24. CCRT: Late Toxicity
Analysis of 230 patients receiving CRT in 3
studies (RTOG 91-11, 97-03, 99-14)
50
43%
Patients (%)
40
30 27%
20
13% 12% 10%
10
0
Any severe Feeding-tube Pharyngeal Laryngeal Death
late toxicity dependence dysfunction dysfunction
>2 yrs post-RT
2012
Machtay M, et al. J Clin Oncol 2008; 26: 3582–3589

25. EORTC 24954
Eligible pts. (previously untreated larynx /hypopharynx) amenable to TL
R<50%
TL + PORT
2 cycles PF* RP TL + PORT
R SEQ
2 cycles PF* RT 70 Gy
A R ≥ 50%
N RC Follow-up
D
O
M
ALT
1cycle RT RT 1cycle RT 1cycle
1cycle
PF** 20 Gy 20 Gy PF** 20 Gy PF**
PF**
RP RC
* P 100mg/m2 d1- 5FU 1000mg/m2 d1-5
** P 20 mg/m2 d1-5 – 5FU 200mg/m2 d1-5
TL + PORT Follow-up
2012
Lefebvre JL et al. J Natl Cancer Inst. 2009

26. EORTC 24954: Global Results at 5 Yrs
Sequential Alternating
(N=224) (N=226)
% %
p-
Events without Events without
value
event event
Survival with
160 30.5 154 36.2 0.15
functional larynx
Larynx preservation 107 53.2 94 59.8 0.10
Progression-free
140 41.0 139 41.8 0.75
survival
Overall survival 125 48.5 122 51.9 0.45
Acute toxicity: SEQ > ALT
2012
Late toxicity: SEQ = ALT
Lefebvre JL et al. J Natl Cancer Inst. 2009

27. Conclusion: How Aggressive Should We be
For Larynx Preservation?
SCRT: ICT followed by CCRT
substancial toxicity best
protocol still unknown place of
biotherapies
CCRT: RT + Px3 substancial toxicity around 80 %
larynx preservation no impact on survival
Triplet ICT: TPF followed by RT still good tolerance/
compliance to Tx around 70 % larynx preservation no
impact on survival
Doublet ICT: PF followed by RT good tolerance/compliance
to Tx around 60 % larynx preservation no impact on
survival
2012
Courtesy of J-L Lefebvre

28. How to Design Future Trials?
Primary endpoint:
• laryngo-esophageal dysfunction-free survival
• events are
- death
- local failure
- laryngectomy
- trach for ≥ 2years
- feeding tube ≥ 2 years
Secondary endpoints:
• overall survival
• progression-free survival
• locoregional control
• time to tracheotomy
2012
• time to laryngectomy
Lefebvre JL and Ang KK. Int J Radiat Oncol
Biol Phys 2009

29. Sequential ICT and CCRT: the Dilemma
Efficacy vs Toxicity
The “best”: The “best”:
TPFx3 RT + Px3
ICT CCRT
??? ???
Options:
Reducing ICT to maintain CCRT?
2012 Reducing CCRT to maintain ICT?
Alternative option for CCRT after ICT?

30. How to Balance Efficacy vs
Toxicity?
• Reducing intensity of ICT:
– Only 1 cycle PF, then decide to TL or
CCRT (cisplatin)
(Worden et al, 2009)
• Reducing intensity of CCRT
– Carboplatin during RT (AUC 1.5/wk)
following 3xTPF
(Posner et al, 2007)
• Alternative enhancement of RT
2012 – Cetuximab during RT following 3xTPF
(Lefebvre et al, 2011)

31. What is the Optimal ST Design?
The Randomized Phase II Study: TREMPLIN
Previously untreated SCC larynx/hypopharynx suitable for TL
Primary endpoint: larynx preservation 3 months after treatment
Secondary endpoints: larynx function preservation and survival
18 months after treatment
RT 70 Gy
TPF
Cisplatin 100 mg/m² on days 1, 22 and 43
3 cycles, 1 cycle q3weeks
T = 75 mg/m² on day 1
≥ PR
P = 75 mg/m² on day 1
R
5-FU = 750 mg/m² on day 1
to 5
RT 70 Gy
Cetuximab 400 mg/m² 1 wk prior to RT
<PR then 250 mg/m² weekly on wks 1 to 7
Total laryngectomy
+ postop RT
2012
Response evaluation by endoscopy and CT scan
Lefebvre et al for GORTEC and GETTEC groups (abstract #6010)
5-fluorouracil, T=docetaxel TL=total laryngectomy, PR=partial response, RT=radiation therapy,
CT=computed tomography

32. Compliance to Treatment
Radiotherapy Cisplatin arm (n=60) Cetuximab arm (n=56)
Not done 2 0
Mean dose 69 (24**-74)
69.5 (56-76)
No of cycles: 7 -
40 (71%)
6 -
4
5 -
4
4 -
1
3 26 (43%)
2012
1 refusal and 1 rapid evolution, **another rapid evoluation,
1
***3 infusion-related reactions
2
Lefebvre et al, ASCO 2011 24

33. Acute Toxicity
CDDP arm (n=58*) CET arm (n=56) p-value
Grade 3 mucositis 25 (43%) 24 (43%) NS
Grade 4 mucositis 2 1
Grade 3 infield skin tox. 14 (24%) 29 (52%) < 0.001
Grade 4 infield skin tox. 1 3
Other tox. Justifying dose
modification
- Renal 9 (15.5%) 0
- hematologic 8 (14.0) 0
- poor general condition 7 (12.0%) 1 (1.7%)
- infusion –related react. 0 3 (5.0%)
- Protocol modifications** 33 (57%) 19 (29%) 0.02
2012
* 2 patients did not start; ** due to acute toxicity. Lefebvre et al, ASCO 2011

34. Assesment of Failures (Intent to Treat)
Last evaluation with a median
At 18 months after end
follow-up of 36 months
of treatment
cisplatin cetuximab p value cisplatin cetuximab p value
arm arm arm arm
Total of local (+/- regional) 5 (8.3 %) 8 (14.3 %) Log-rank: 7 (11.7 %) 12 (21.4 %) Log-rank:
failures 0.30 0.14
Feasible salvage 0/4* 7/8 0.01 1/6* 9/12 0.04
Total laryngectomy (1 refused)
Successful salvage 0/1 7/8
total laryngectomy
Ultimate local failure rate 6 (10 %)* 5 (8.9 %) NS
Regional failure alone 5 (8.3 %) 5 (8.9 %) NS 5 (8.3 %) 5 (8.9 %) NS
Distant metastases 2 (3.3 %) 2 (3.6 %) NS
Second primary tumor 3 (5 %) 3 (5.3 %) NS
2012
* Data missing for 1 patient lost to follow-up at 5 months
Lefebvre et al, ASCO 2011

35. Overall Survival (Intent to Treat)
2012

36. Conclusions
• Upfront surgery remains the best option in some
cases (cases for partial surgery, transglottic and
T4)
• Salvage surgery plays a major role in organ
preserving treatments
• Organ preserving strategies do not jeopardize
survival and disease control but, to date, no non-
operative treatment has provided a better
survival that upfront surgery
• Distant metastases remain a concern
2012
• Non-operative treatments must be evaluated in
the light of disease control AND of survival AND
of quality of the function