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Organ-Preservation Strategies in head and neck cancer
Teresa Bonfill Abella
Oncologia Mèdica
Parc Taulí Sabadell. Hospital Universitari
Larynx Hypopharynx
Witch is the optimal primary endpoint? - Larynx preservation rate - Larynguectomy- FS? - Survival Rate at 2, 5, 10 years? - QoL ………………………………………….
“The goal of treatment is to achieve larynx preservation with good function without compromising survival”
Summary of the Relevant Literature
Surgery + RT Surveillance
PF x 3
no response surgery + RT surveillance
response RT +/- salvage surgery
3 randomized studies:
- VA - EORTC 24891 - GETTEC
larynx
hypopharynx
T3 larynx
VALCSG. N Engl J Med 1991
Lefebvre JL et al. J Natl Cancer Inst 1996
Richard JM et al. Oral Oncol 1998
Induction chemotherapy
New England Journal of Medicine 1991; 324: 1685-1690
332 pts, laryngeal SCC stage III/IV
Surgery
Surgery +/- RT
IC x 2
Cisplatin 100mg/m2, D1
5FU 1000mg/m2/d x 5d q3w
RT: 5000cGy/25fx Adjuvant RT
Definitive RT
RT: 6600-7600cGy
IC x 1
Residual disease Poor
respond
2yr DFS OS Recur at
primary
Recur at
regional
Distant
mets Laryngectomy-
free survival
Surgery 75% 68% 2% 5% 17%
IC RT 65% 68% 12% 8% 11% 39%
p value 0.12 0.98 0.001 NS 0.001
T1/T2 9%
T3 65%
T4 26%
Glottis 37%
Supraglottis 63%
Veterans Affairs Laryngeal Cancer Study Group
LPR: 64% (2y)
Journal of National Cancer Institute 1996; 8: 890-899
194 pts, hypopharynx SCC stage II/III/IV
Surgery
Surgery +/- RT
IC x 2
Cisplatin 100mg/m2, D1
5FU 1000mg/m2/d x 5d q3w
RT: 5000cGy/25fx Adjuvant RT
Definitive RT
RT: 7000cGy
IC x 1
Residual disease Poor
respond
5yr DFS OS Recur at
local
Recur at
regional
Distant
mets Laryngectomy-
free survival
Surgery 32% 35% 17% 23% 36%
IC RT 25% 30% 12% 19% 25% 42% (2y)
35% (5y)
p value NS NS NS NS 0.041
T2 20%
T3 75%
T4 5%
Pyriform
sinus 78%
Aryepiglottic
fold 22%
EORTC 24891
Trial/ site of tumour
N Therapy aproach Larynx Preservation
LFS
Survival Difference
VALCSG
(larynx)
332 S RT
vs
PF1x3 RT
64%(2y)
39%(2y)
No difference
EORTC 24891 (hypopharynx)
202 S RT
vs
PFx3 RT
40,5% (5y) 42% (2y)
35% (5y)
No difference
1CDDP 100mg/m²/ev d1
5-FU 1000mg/m²/ev d 1-5 (ic)
every 3w x 3courses
Induction PF + RT can be effective in preserving the
larynx in a high percentage of patients, without
compromising overall survival
Induction chemotherapy
PF induction
RT-CT concomitantly (cisplatin days 1, 22 and 43)
RT
no response surgery + RT surveillance
response RT +/- salvage surgery
RTOG 91-11 (USA) larynx
Forastiere A et al. N Engl J Med 2003
Chemoradiotherapy
T2 12%
T3 78%
T4 10%
Supraglottis 69%
Glottis 31%
N=547pt 1CDDP 100mg/m²/ev d1
5-FU 1000mg/m²/ev d 1-5 (ic)
every 3w x 3courses
2yr DFS OS Intact
larynx
LR
control LFS
Distant
mets
A: RT 27% 56
% 70% 56%
53%
38%
(5y)
22%
B: CCRT 36% 54
% 88% 78%
66%
45%
(5y)
12%
C:
ICRT 38%
55
% 75% 61%
59%
43%
(5y)
15%
p
0.02(C v
A)
0.006(B v
A)
NS
0.005(B v
C)
0.001(B v
A)
0.004(B v
C)
0.001(B v
A)
0.49(BvC)
0.01 (AvB)
0.03(B v
A) Difficulties in Speech/swallow : similar (2y) 15%
RTOG 91-11 (USA) larynx
Chemoradiotherapy
Forastiere A et al. N Engl J Med 2003
Toxicity: - The rate of high grade toxic effects was greater in Ch-based regimens
81% (Chi->RT), 82% (Ch-RT) & 61% (XRT) - The mucosal toxicity of concurrent RT-CDDP was nearly twice as
frequent as the mucosal toxicity of the other two treatments during RT
- No differences in late toxicity or speech or swallowing function were demonstrated between treatment groups
Calais G, et al. ASCO 2006, abstract 5506.
GORTEC 2000-01
Induction CT Larynx Preservation
Primary Objective: larynx preservation rate
Larynx or hypopharynx
tumors
Resectable tumors or
nodes requiring total
(pharyngo[P] laryngectomy)
No previous treatment
TPF arm Docetaxel (75 mg/m² d1)
Cisplatin (75 mg/m² d1)
5-FU (750 mg/m²/dx5)
Q 3 weeks x 3 cycles
PF arm
Cisplatin (100 mg/m²) 5-FU (1000 mg/m²/dx5)
Q 3 weeks x 3 cycles
Non-responders:
Total
(P)laryngectomy
+ post-op RT
Responders:
RT
Response
to
induction
treatment
Yes
No
Induction chemotherapy
Pointreau et al. ASCO 2006
T2 18%
T3 67%
T4 15%
Induction chemotherapy GORTEC 2000-01
Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03;
Calais G, et al. ASCO 2006, Abstract 5506.
GORTEC 2000-01
Grade 3/4 Acute Toxicities
NCI/CTC Grade 3/4* TPF PF p
Mucositis 4.6 7.8 0.49
Neutropenia 55.6 37.3 0.01
Febrile neutropenia 13.9 7.8 0.24
Thrombocytopenia 1.9 7.8 0.09
Deaths 3.6 2.9 0.71
% of patients
*Among patients treated with RT alone, no differences were observed between
the 2 arms in: xerostomia, fibrosis, larynx edema, dysphagia, % of patients with
permanent feeding tube.
Induction chemotherapy
Sequential therapy for locally advanced larynx and hypopharynx cancer: Subgroup analysis from TAX 324
study
Induction chemotherapy
TAX 324
Induction chemotherapy
TAX 324
ASCO 2008
-Significant improvement in PFS (Hazard Ratio 0.61 (0.40-0.96) p=0.033 -Strong trend for OS (Hazard Ratio 0.67 (0.41-1.11) p =0.12
Five phase III trials
(VALSG, EORTC 24891, RTOG 91-11, GORTEC 2000-01, TAX 324)
STUDY LFS LPR
VETERANS (L)
EORTC 24891 (H)
RTOG 91-11 PF (L)
RTOG 91-11 QT+RT (L)
GORTEC 2000-01 PF (L&H)
GORTEC 2000-01 TPF (L&H)
TAX 324 PF (L&H)
TAX324 TPF (L&H)
39% (2y)
42% (2y) 35% (5y)
59% (2y) 43% (5y)
66% (2y) 45% (5y)
37% (3y)
53%(3y)
32% (3y)
52%(3y)
64% (2y)
75%(2y)
88%(2y)
57% (3y)
70%(3y)
TREMPLIN: French randomized phase II study of laryngeal preservation
TPF x 3
No resp. S + PORT
Resp.
RT + cetuximab
RT + cisplatin
Randomized phase II, GORTEC-GETTEC)
Larynx/hypopharynx suitable for TL
N=153
ASCO 2009 i ASCO 2011 JCO 2013
• From these studies we have learnt that:
None of the ch-based protocols has provided better results than surgery
except in terms of larynx preservation
- Ch combined with RT has allowed to preserve a significant number of larynx without compromising survival
- PF followed by RT and Ch-RT show similar efficacy in LFS - LCR and LPR were significantly improved with Ch-RT
- Ch decreased the incidence of DM without impact in OS
- TPF is better than PF in LFS & PFS - Chemoradiotherapy & Induction Chemotherapy are alternatives
-TPF-based ICT followed CRT or BRT was feasible but had
substantial overall toxicity
There is currently no good evidence base from larynx preservation trials with which to assess
the functional outcomes achieved with different larynx preservation strategies
The Oncologist 2010;15 (suppl3): 25-29
Suggested approaches to management
T1, T2
• TT Intent to preserve the larynx
• RT or larynx preservation surgery
• tt selection depends on: pt factors, local expertise & rehabilitation services
• Concurrent Ch-RT only in:
– Stage III, T2 N+ pts whom total LT is the only surgical option OR larynx-preservation surgery is expected to yield an unsatisfactory functional outcome OR organ-preservation surgical expertise is unavailable
“Narrow –margin excision” followed by postoperative radiation therapy IS NOT an acceptable treatment
approach”
T3, T4
• Organ preservation surgery, Ch-RT , Chi RT and Rt alone offer potential for larynx preservation without compromising survival
• Tt selection depends on: pt factors, local expertise and rehabilitation services
• Pt with tumor penentration through cartilage into soft tissues are considered poor candidates for larynx-preservation approach. LT is recommended in these cases
Factors associated with decreased larynx-preservation outcomes:
• Male gender
• Anemia (at start of treatment)
• Smoking
• Advanced T stage
• Clinically detectable impaired vocal cord mobility
• Subglottic extension
• Involvement of anterior commissure
• Large tumor volume
• Invasion of specific anatomic sites (determined by CT or MRI)
Recommended management approach for treatment of resectable T3-4 N0-3 laryngeal cancer
JCO, Vol 31, No7 (march1), 2013:pp840-844
CONCLUSIONS
• Larynx-preservation therapy is intended to offer improved function and quality of life without compromising survival.
• All patients with T1-T2 should be treated initially with intent to preserve the larynx.
• Pt with T3- selected T4 should be offered a larynx-preservation treatment option.
• Chemoradiotherapy & Induction Chemotherapy are alternatives
CONCLUSIONS
• Preservation of the laryngeal structure is not considered a functional success if persistent dysphagia, aspiration, or chronic tracheostomy.
• Selection of treatment for laryngeal cancer should always depend on patient factors, local expertise, and appropiated support and rehabilitative services.
• A multidisciplinary team with specialized expertise is necessary to ensure optimal outcomes.