ORGAN PRESERVATION IN LARYNGEAL CANCER

1. Organ
Preservation in
Laryngopharynge
al cancers
DR .RAHUL PATHADE
TATA MEMORIAL HOPSITAL

2. Flow of seminar
 Anatomy
 Epidemiology
 Staging
 investiagtions
 Case scenario
 Different treatment modality
 Outcomes
 Follow up

3. Anatomy

4. AJCC Cancer Staging Manual. 8th ed.
AJCC TNM classification of carcinoma of the larynx
Supraglottis

5. 5
Glottis

6. Subglottis

7. 7Hypopharynx

9. Stage Grouping
Early
stage
Advanced
stage
T1 T2 T3 T4a T4b M1
N0 I II III IVA IVB IVC
N1 III III III IVA IVB IVC
N2 IVA IVA IVA IVA IVB IVC
N3 IVB IVB IVB IVB IVB IVC
EARLY
METASTATIC

10. • VC involvement is a late
phenomenon, however
paraglottic spread early.
• Rich lymphatics b/l- Level
II and III
Supraglottis
• Slow growing
• Minimal lymphatics, Ln
involvement incase of
extension to supraglottis
and subglottis
Glottis
• Lymph nodes Delphian
node (pre tracheal) anteriorly
• Posteriorly to para tracheal
level IV
Subglottis

11. 11• At diagnosis, less than 15 percent
of hypopharyngeal cancers are
confined to the hypopharynx.
• Regional lymph nodes -65 %
Distant spread-20 percent
• More likely to spread to the
retropharyngeal (PPW) and level V
lymph nodes
Hypopharynx

12. Burden of disease
LARYNX PHARYNX(
Other than
NPx)
Incidence Incidence
Worldwide(
% of all
cancers)
1.1 1
India 4.8 6.6
12
GLOBOCAN 2012
Overall incidence of laryngeal ca in India in 2012- 25,446
Overall incidence of pharyngeal ca in India in 2012- 38,691

13. Diagnostic work up
 History and physical exam.
 Local Examination
 Oral examination
• Other regional pathologies, synchronous oral cavity or
oropharyngeal tumors, might be associated.
• Neck examination
 Examine size, location, number of palpable lymph
nodes in all cervical and supraclavicular areas.
 Palpate and wiggle the larynx from side to side for
laryngeal crepitus.
 Head/ CNS examination
 Assess cranial nerve function.
 Assess jaw mobility.
 General examination for distant metastases and comorbidities

14.  IDL-to assess extent of dis.
 Ba swallow-to map mucosal extent of disease.
 Flexible endoscopy - exact extent of ds, assess areas not
seen on IDL / hopkins [PFS apex, PC region], and obtain
biopsy.
 Imaging CT-[head and neck]
tumor volume
cartilage and bone invasion.
Extralayrngeal invasion
nodal disease [preferred for cartilage invasion]
 MRI - extracapsular LN tumor extension.[prefered for
soft tissue]
cricoid involvment.
 PET-CT for evaluation of post Rx residual disease/recurrent
ds.

15. Speech and swallowing
evaluation
A)100ml water swallow test-
1)swallow volume
2) swallow capacity (mL/sec = mL swallowed/ time taken
(3) swallow speed (time per swallow = time taken
/number of swallows.
B)Fibreoptic endoscopic evaluation of swallowing (FEES)
c) VFSSVideofluoroscopic Swallowing Study

16. PAS 16
Fig. 1. Penetration Aspiration Score (PAS) by primary site
and tumor
stage. Data represent the mean 6 standard error of mean.
OC ¼ oral cavity; OP ¼ oropharynx

17. VFSS

18. Case scenario
 Patient is a 50-year-old man with a 4month history of a hoarse
voice, odynophagia/throat pain. He has a history of Beedi
smoking 15beedi/day.
 Able to have solid food without any cough,no difficulty in
breathning.
Investigations:
1. Direct Laryngoscopy: A large,
friable mass was found centred in
the left supraglottic region,
extending from left Ary-epiglottic
fold to left pyriform sinus. Tumour
extension was present just to the
level of the true cords. Cord
mobility impaired on left side.

19. 2.Biopsy-MDSCC
3.Barium swallow- Not s/o aspiration
4.CT neck- 4.9 X 4.0-cm mass centred in
the left supra-glottic larynx. B/l
adenopathy was noted primarily at level
II but with smaller concerning
adenopathy, especially in low left level
III. The tumour has eroded a small area
of the inner table of the thyroid cartilage.
5. Chest Xray -Normal
20
Diagnosed as Ca Lt Supraglottis cT3 cN2c M0 MDSCC

20. Various Treatment modalities in Locally
Advanced Carcinoma Larynx and
Hypopharynx
1.Total laryngectomy +/- PORT
2.Organ Preservation startegies:
a. Conservative Surgery
b. Definitive RT
c. Induction chemotherapy (ICT) followed by RT
d. Concurrent chemo-RT
e. ICT followed by CTRT
f. Role of Targeted therapies
g. Altered fractionation

21. For the above case, TL would have been the
treatment of choice in 1990’s…
The conventional treatment for stage III and IV Ca larynx consisted of
Total laryngectomy +/- PORT.
With 5 yr survival rates ranging upto 50% (Jesse/Vermund et al)
In T3N0, RT alone showed similar survival .(40-70%)With lower
survival in advanced cases.(Harwood/Stewart et al)
However TL is associated with substantial functional disability,including
1.loss of natural voice
2.alterations in deglutition and
3.permanent tracheostomy.
Hence there was a need for alternative form of treatment without
reduction in survival.

23. With the aim of good control rates along
with laryngeal preservation..
Several pilot studies of addition of chemotherapy before
surgery/radiation had shown
1.High rates of complete regression
2.Prolonged survival
With this approach in mind,
Veterans Affair Laryngeal Cancer Study was launched.

24. 322 Patients (Stage
III and IV)
166
Induction
chemotherapy f/b
Definitive RT
If PR/CR after 2 #
3rd cycle f/b RT
If no response
Surgery f/b PORT
166
Upfront Surgery +
PORT
R
Cisplatin(P)
+5FU(F) on Day
1,22,43

25. 26
• In the induction chemotherapy plus RT group,
at 2 years 64% of all patients retained their
larynxes, and 64% were free of disease.
Stage/T size Rate of Salvage
laryngectomy
III/IV 29%/44%
T3 or lesser/T4 29%/56%

26. Criticism
 The control rates for T3 cancers (65% of enrolled patients)
were similar to historic published results with radiation alone
and were a basis for criticism by radiation oncologists who
argued that a comparator radiation-alone arm was needed.
27
This study set the stage for further larynx preservation
studies and established induction chemotherapy as standard
of care.

27. EORTC (1996)
24891
28
194 Patients with T2-
T4, N0-N2b,N3
squamous cell
carcinoma of the
aryepiglottic fold and
PFS
Surgery f/b RT
94
ICT PF X 3 cycles
F/B Definitve RT
100
Lefebvre et al JNCI 88, 890, 1996.
R

28. 29
• There was no difference in
overall survival @ 10 years.
• Rates of functional larynx in ICT
arm @ 10yrs-27%
Conclusions: Larynx preservation without jeopardizing survival
appears feasible in patients with cancer of the hypopharynx
with induction chemotherapy.

29. Such was the popularity of larynx
preservation approaches…

30. 1998- GETTEC (Groupe d’Etude des
Tumeurs de la Tête et du Cou)
The study had to be prematurely abandoned due to a strong patient
preference for organ preservation over surgical resection.
Although, the findings were not adequately powered, the study
demonstrated significantly poorer survival in the induction chemotherapy
arm than those who underwent primary surgery (2 year survival 84% in the
surgery group vs. 69% in the chemotherapy group).
All the patients in this study had vocal cord fixation,(
less than 60% patients in VALCSG )

31. Pignon et al Lancet, 2000
• 3 Trials , N-602, Median follow-up
of 5·7 years
• Larynx Preserved in 23% of pts
alive at 5 yrs
• There was significant heterogeneity
between the three trials (p=0·05).
@ 5yrs ICT f/b
RT
Sx P value
OS 39% 45% 0.1
DFS 34% 40% 0.05

32. NACT has minimal impact on
overall survival…..
There was need for more intensive
local therapy..

33. MACH NC 2000
Level one evidence of significant benefit of addition of CT in terms of OS
Pignon et al, Lancet,2000
Meta-analysis of locoregional treatment with and without chemotherapy: effect on
survival

34. 35
Head and Neck Intergroup Trial
RTOG 91 - 11
518
Stage III/IV
glottic and
Supraglottic
Ca
ICT(PF) f/b RT
173
CTRT
172
RT alone
173
The primary end point used for sample size calculation
was the composite end point, laryngectomy-free survival
Forastiere A et al.NEJM 2003
R

35. With concurrent therapy, there was an absolute
reduction in the rate of laryngectomy of 43 %
DFS is better with chemotherapy ( either sequential or concomitant) than RT
alone. (P-0.02 and P-0.006 resp.)
Distant Metastasis was more in RT alone arm than CTRT (P-0.03)
There was no difference in speech impairment across all arms.
However delayed recovery of swallowing function was reported in CTRT
arm (QOL data)
Outcomes@ 5 yrs Induction Concomitant RT
Laryngeal
preservation
72% 84% 67%
Laryngectomy free
survival
43 45 38
Overall Survival 55 54 56
Locoregional
control
61 78 56
Progression free
survival
38 36 27
Mucositis grade 3-
4 during RT
38 Pts 73 pts 41 pts

36.  After a median follow-up period exceeding 10years, there was no
significant difference in overall survival.
 After about 4.5 years, the curves begin to separate favoring induction,
although the difference is not statistically signifi-cant.
 LP(81%) and local control rates were significantly higher with
concomitant cisplatin and RT
 Laryngectomy free survival , no difference between the
concomitant arm (23% @10yrs) versus ICT arm (28.9%), HR-
1.05,Worst in RT alone group.
 Late toxicity was comparable across all arms.

37. CTRT
better
CTRT = ICT F/B RT
COMPARABLE CTRT
better

38. MACH NC 2011-Site wise
anlaysis

39. MACH-NC - Laryngeal cancer
• 3216 patients with laryngeal
cancer and 61 comparisons are
included.
• The HR of death associated with
chemotherapy is 0.87
• Absolute 5-year overall survival
benefit of 4.5% increasing from
42.5% to 47.0%.
Blanchard et.al. Meta-analysis of chemotherapy in head and
neck cancer (MACH-NC): A comprehensive analysis by
tumour site; Radiotherapy and Oncology 100 (2011) 33–40

40. MACH-NC - Hypopharyngeal
cancer
• The HR of death
associated with
chemotherapy is 0.88
• Absolute 5-year overall
survival benefit of 3.9%
Blanchard et.al. Meta-analysis of chemotherapy in head and
neck cancer (MACH-NC): A comprehensive analysis by
tumour site; Radiotherapy and Oncology 100 (2011) 33–40

41. What about Toxicity Profile??
42
1. Although CRT improves LRC and OS, and allows for organ preservation, toxicities are
increased compared with RT alone. The most common acute grade 3 to 4
complications (leukopenia, anemia,mucositis, and dysphagia) are
increased from14% to 43% over RT.
2. CRT patients were more likely to have a diet limited to soft foods or liquids,or
require gastrostomy tube use at 1 year (26% compared with 18%with RT), but at 2
years there were no differences between the treatment groups (16% with CRT, 14%
with induction followed by RT and 15% with RT)

42. Role of altered fractionation…

43. MARCH meta-analysis
 15 trials with 6515 patients were evaluated.
 Median follow-up - 6 yrs.
 Tumours sites - mostly oropharynx and larynx (44 and 34%
respectively)
 74% had stage III–IV tumours

44. MARCH meta-analysis
 Absolute benefit of 3·3% and 3·4% at 2 and 5 yrs with altered
fractionation, with greatest benefit for hyperfractionated RT (9.4% at
5 yrs)
 Altered fractionation was most beneficial in younger patients (Age
<50 yrs) with good performance status (KPS > 70) – same as in
case of conc CTRT

45. Although altered fractionation served as a good option
in patients in which chemotherapy could not be given,
better options were needed …
There were 2 options:
A. Intensification of Induction chemotherapy
B. More intensive local therapy Induction f/b concomitant
chemotherapy .

46. EORTC 24971/TAX 323 Study
Group* 2007 Vs TAX 324
Addition of docetaxel to PF induction chemotherapy in patients
with unresectable squamous-cell carcinoma of the head and neck
improved survival and was better tolerated than the classic PF
regimen.

47. 220
Advanced Ca Larynx
and Hypopharynx
cases requiring TL ICT using Docetaxel
+Cis+FU
103 x 3 cycles
RT alone or
concomitant CTRT
ICT using Cis +5FU
110
RT alone or
concomitant CTRT
GORTEC 2000-01,J Natl Cancer Inst 2009;101: 498 – 506
Those pts who
recovered
laryngeal
mobility
Primary End point: 3yr larynx preservation rate,
R

48. 51
Outomes TPF PF P value
Larynx
preservation
@ 3 years
70.3% 57.5% 0.03
Overall
response to
ICT
80% 59% 0.002
TPF >> PF

49. GORTEC 2000-01
 OS and DFS were not statistically significantly different
 Both regimens were comparable in terms of late toxicity
rates
 More patients in the TPF group recovered to normal
larynx mobility (42.7% vs 29.1%, respectively; P = .034).
J Natl Cancer Inst 2009;101: 498 – 506
Long Term results @ 105 months
Laryngeal dysfunction free survival was
significantly better in TPF arm.
Statistically fewer grade 3–4 late
toxicities of the larynx occurred with the
TPF
In patients with advanced larynx and hypopharynx
carcinomas, TPF induction chemotherapy was superior to the
PF regimen in terms of overall response rate.

50.  TPF significantly improves OS, PFS, loco-regional and distant failure
compared with PF.
 TPF is associated with a better compliance.
 More patients in the TPF group proceded to conc CTRT, likely
reflecting the higher response rates. Blanchard et.al. J Clin Oncol 31. © July, 2013

51. Would induction chemotherapy (IC) be more
likely to demonstrate an improvement in
survival if two other conditions were met??
Use of a CRT regimen achieving high
rates of locoregional control and
Treatment of patients at greatest risk for
distant metastatsis

52. 2013 - PARADIGM Lancet Oncol 2013; 14: 257–
64

53. 2014 – DeCide[Docetaxel- Based Chemotherapy Plus or Minus IC
to Decrease Events in Head and Neck Cancer], JCO
285
Non-metastatic
N2,N3 SCCHN ICT ( 2 TPF) F/B
CRT
CRT
Majority of pts were
oropharyngeal
cancers , Stage IV A
Concurrent chemo
RT regimen n both
arms included
Docetaxel, 5FU,
Hydroxyurea
R

54. 3-year Outcomes
Endpoint IC arm
(%)
CRT arm
(%)
HR 95% CI P value
Overall Survival 75 73 0.92 0.59-
4.42
0.70
Distant-Failure Free Survival 69 64 0.84 0.56-
1.26
0.39
Recurrence Free Survival 67 58 0.76 0.52-
1.13
0.18
Cumulative incidence of distant
failure
10 19 0.46 0.23-
0.92
0.025
Cumulative incidence of
locoregional failure
9 12 0.79 0.37-
1.68
0.55
 Only grade 3-4 leukopenia and neutropenia rates were significantly higher in
induction chemotherapy.
 Although there was a statistically significant improvement in cumulative incidence
of distant metastases in the induction chemotherapy arm, there was not
improvement in overall survival.

55. Why the negative results?
 Only 79% of patients received the intended two doses of
NACT.
 Unrealistic expectation of 15% absolute increment in 3-year
overall survival with NACT. (The absolute survival benefit of cisplatin
and fluorouracil induction chemotherapy in accordance with meta-analysis of
chemotherapy in head and neck cancer was 2.4%.)
 Believing that adding taxane to this regimen would lead to an
absolute improvement of more than 10% in overall survival
was therefore unrealistic.

56. Meta-analysis of Sequential vs Concomitant
chemotherapy in LA-HNSCC
Meta-analysis Induction chemotherapy with concurrent
chemoradiotherapy versus concurrent chemoradiotherapy for
locally advanced squamous cell carcinoma of head and neck,
sciientific reports, Nature,2013
Five prospective randomized
controlled trials (RCTs) with
922 patients were included in
meta-analysis-
No significant differences
in OS,PFS, LRR
ICCCRT could increase
risks of grade 3–4 febrile
neutropenia (P = 0.0009) and
leukopenia (P = 0.04).
Distant metastasis rate
(DMR) decreased (P = 0.006)
and complete
response rate (CR) improved
(P = 0.010) for IC with CCRT.

57. Meta-analysis Induction chemotherapy with concurrent
chemoradiotherapy versus concurrent chemoradiotherapy for
locally advanced squamous cell carcinoma of head and neck,
sciientific reports, Nature,2013

58. • Pts who had successful organ preservation tended to have
better scores on all domains of SF-36 compared to laryngectomy
• Pts who had successful organ preservation are associated with
better quality of life related to freedom from pain, better
emotional well-being and lower levels of depression.
Terrell JE et al. Arch Otolaryngol Head Neck Surg. 1998

59. Role of biological modifiers??
In view of increased toxicities with concurrent
chemoradiation thereby affecting OS and QOL
Role of Biological modifiers with RT was explored in
Organ preservation.

60. 3 # TPF
(153)
Responder
A
ChemoRT(60)
(Cisplatin + RT)
B
BioRT(56)
(Cetuximab+RT)
Non responder Surgery
Primary end point-
larynx preservation at
3 months
Secondary end
point-Larynx
dysfunction free
survival at 18month
-OS at 18 months
Stage III/IV
larynx and
hypopharyngeal
cancer.
--Despite a higher number of local failures in the B arm,after salvage surgery, the
ultimate local failure rate seemed comparable.
-Comparable grade 3-4 toxicities in both arms. (more in field skin toxicity in
BioRT arm)
R

61. 65
Cisplatin Cetuximab P value
Primary endpoint
Larynx
preserved(without
tumour)
95% 93% 0.63
Secondary
endpoint
Functional Larynx
( Without tumour,
NGT,
Tracheostomy)
87% 82% 0.68
Survival 92% 89% 0.44
Raised the possibility that for larynx cancer, EGFR inhibition/RT may be
inferior to cisplatin/RT for achieving local control,both cetuximab/RT and
cisplatin/RT were difficult to administer after induction TPF.
However BioRT is better tolerated than CTRT

62. DARS Sparing IMRT
 Significant correlations were observed between videofluoroscopy-
based aspirations and the mean doses to the Pharyngeal
constrictors, as well as the partial volumes of these structures
receiving 50–65 Gy
 The highest correlations were associated with doses to the superior
PC (p = 0.005).

63. Coming back to our case
scenario...
Ca Lt Supraglottis cT3 c N2c M0 MDSCC
(left VC impaired mobility, minimal thyroid
cortical erosion.)

64. 68
Author
(year)
N Site Stage Treatment Larynx
Preservation
P
value
Overall survival
VALCSG
(1991)
332 Larynx Stage
III/IV
PF->RT vs
S->RT
64% NA 68% @ 2yrs
68% @ 2yrs
EORTC
24891
(1996)
202 HPx II-IV PF->RT vs
S->RT
22% @ 5yrs NA 38% @ 5yrs, 13.1%@
10yrs
33% @5yrs, 13.8% @
10yrs
GETTEC
(1998)
68 Larynx II-IV PF->RT vs
S->RT
42%(Median
8YRS)
NA 69% @ 2yrs
84% @2 yrs P-0.006
RTOG 91-
11
547 Larynx III-IV PF->RT vs
CRT vs
RT
67.5% @10yrs
82%@ 10yrs
64% @ 10yrs
0.005
<0.00
1
39% 10yr
27% @ 10y
31.5%@10y
GORTEC
00-01
(2009)
213 Larynx
Hypopha
rynx
III-IV PF->RT vs
TPF->RT
57% @ 3y
70% @ 3y
0.03 60% @ 3y
60% @ 3 y
TREMPLIN
(2012)
153 LA
HPx
III-IV TPF->CRT vs
TPF->Cet RT
93% @ 3m
96% @ 3m
NS 85% @1.5YRS
86%

65. Factors deciding choice of
treatment
Patient factors
• Age
• Performance
Status
• Comorbidity
• Previous Rx
• Reliability for F/U
• Pt.’s choice
• Pt.’s occupation
• Second Primary
Disease
Factors
• Stage
• Site
• Volume
• Cord Mobility
Treatment
factors
• Physician’s
Expertise
• Cost and
Feasibility
• Treatment
morbidity

66. Factors associated with
decreased larynx preservation
outcomes. Male/ Smoker
 Anemia , at start of treatment
 Advanced T stage(T4)
 Clinically detectable impaired vocal cord mobility(Higher chances
of aspiration)
 Subglottic extension.
 Involvement of anterior commissure

67. Figures we are expecting…
3 year outcomes
TL+/- PORT (VALSG)
Overall survival 60-70%
Laryngeal preservation 0%
Organ preservation (RTOG 91-11 &
GORTEC 00-01)
Overal survival 70-75%
Laryngectomy free
survival
Upto 60%
Functional larynx 40-45%
Salvage laryngectomy 15-30%
Sever late dysphagia @ 5years
Upto 25%

68. Given the cricoarytenoid involvement, partial laryngectomy would not be a good option. Thus,
surgery should be total laryngectomy.
With a fixed cord, no aspiration and laryngeal structural integrity maintained we can go for
organ preservation.
We would recommend immediate smoking cessation.
Considering he is a motivated, robust patient, we would offer larynx preservation by
Concurrent chemo-radiation using DARS sparing IMRT to reduce toxicities if feasible. (
RTOG 91-11 10 yr results have shown comparable LFS with both CTRT/ICT, however
OS benefit with CTRT for larynx as shown in MACH-NC 2011 update)

69. ICT f/b CCRT??
 Since the patient is borderline for breathing/swallowing ,
delay in starting CTRT could increase the risk of dysponea
 Also Pt has N2c disease higher risk for distant mets
 Taxane based induction chemotherapy followed by response
assessment is a good option too.( Lower DMR, Higher CR
 Besides it gives us the benefit of bioselection.

70. Eligibility criteria for larynx
preservation
 Laryngeal or hypopharyngeal T2–T3 up to T4 tumors,
 Without massive cartilage invasion or extension to soft tissues,
 Without laryngeal dysfunction (tracheostomy, nasogastric tube,
or inhalation pneumonia)
 Age <70 years or pts fit for CT and performance status (WHO)
<3

71. When not to go ahead with
it…
 Gross cartilage invasion
 Dysfunctional larynx
 patients who prefer avoiding RT
 those who either cannot tolerate CT or refuse CT
 status manifested by severe airway compromise requiring a
tracheostomy or enteric feeding, are poor candidates for LP

72. Why not go ahead with organ
preservation for all patients?
 Importance of preservation of functional larynx.
 To avoid long term dependence on feeding tubes and
tracheostomy.
 Necrosis post CTRT in cases with involvement of
tracheal cartilage.

73. Voice Rehabilitation after TL
 Goal –Restoration of voice and speech production.
 There are three major approaches used to restore oral
communication, and many patients learn to use all three methods:
1. ●The electrolarynx(Most common)
2. ●Tracheoesophageal puncture (TEP) with voice prosthesis
3. ●Esophageal speech
 Selection of the mode of alaryngeal communication should be
based upon an individual's specific needs, personality, physical
capabilities, level of independent functioning, family support, and
motivation.

74. Conclusion
 There is no one standard larynx preservation treatment
accepted worldwide.
 CTRT to be preferred with IMRT for optimal DARS sparing
and careful assessment of DARS dysfunction
 Role of NACT – Bulky disease,Higher chances of distant
mets,Gross exolaryngeal spread without cartilage
destruction
 Bio RT may be preferred in case poor tolerability to
chemoRT is expected.

75. Thank You