Carcinoma Larynx; Evidence based management Staging - Surgery - Adjuvant therapy - Organ Preservation - Altered fractionation, chemotherapy - Radiotherapy (RT) techniques, Role of IMRT

1. Carcinoma Larynx
- Management
Dr. Animesh Agrawal

2. Stage Grouping
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III
T3 N0 M0
T1-3 N1 M0
Stage IVA
T4a N0-1 M0
T1-4a N2 M0
Stage IVB
T4b any N M0
any T N3 M0
Stage IVC any T any N M1
Early
stage
Advance
d stage

3. Management
Surgery
Radiotherapy
Chemotherapy

4. Treatment goals
Primary goal
• Cure / Local control
Secondary goal
• Organ Preservation.

5. EARLY STAGE (I-II)(T1-T2, N0)
• Single Modality
- Surgery or RT
• Choice depends on
- Tumor factors
- Patient factors
- Physician factors
• Equally effective: No randomised trials for surgery vs. RT.
• Each modality can salvage the other in case of local failure.

6. ADVANCED STAGE:(III/IV)
T1-2, N1-3 / T3-4, N0-N+
Multi Modality:
• Pre-op RT f/b Surgery
• Surgery f/b Post-op RT/CT-RT
• Neoadjuvant chemotherapy f/b surgery
• Neoadjuvant chemotherapy f/b RT
• Radiotherapy with concurrent chemotherapy
• Radiotherapy with biological therapy

7. Surgical treatment - approaches
• Supraglottic laryngectomy
• Extended supra glottic laryngectomy
• Cordectomy
• Vertical partial laryngectomy
• Supracricoid partial laryngectomy
• Total laryngectomy
Supraglottic larynx
Glottic Larynx

8. Surgery Indication Parts removed
Supraglottic (horizontal
partial) laryngectomy
(SGL)
• Voice preservation
surgery for early
supraglottic lesion.
• Removes epiglottis, AE
folds, false cords, upper
1/3-1/2 of thyroid cartilage.
• Hyoid bone may be
removed if epiglottic space
involvement.
Extended Supraglottic
Laryngectomy (Extended
SGL)
• Supraglottic lesion with
< 1 cm base of tongue
invasion
• Same as SGL with removal
of Ipsilateral BOT up to
circumvallate papillae
Surgery for Sugraglottic lesions
(contd: for Glottic lesions)

9. Surgery Indication Parts removed
Cordectomy • Small lesion or early T1a lesion of
middle 1/3rd of vocal cord
• Involved vocal cord
Vertical partial
laryngectomy
• Lesion of mobile cord extending to
anterior commissure, i/l vocal process
and anterio-superior portion of arytenoid.
• Subglottic extension < 5 mm.
• Fixed VC lesion not crossing the
midline.
• Not involving more than anterior third of
opposite cord.
• Removes adjacent
thyroid cartilage.
• Removal one TVC
and up to 1/3 or
5mm of other TVC
Supracricoid
partial
laryngectomy
(SCL)
• Selected T2 and T3 glottis disease
• Involving b/l post commissure only
• Lesion on mobile cord extending to ant.
commissure
• Cord fixation in an otherwise T2 lesion
• Both true and false
cords + entire
thyroid cartilage
• May remove the
arytenoids
Total
Laryngectomy
• Lesions with transglottic or extensive
(>1cm) subglottic extension
• Salvage for RT failure
• Total laryngectomy
+ removal of
varying amount of
pharyngeal wall

10. Combined modality treatment
• Pre-op RT f/b Surgery
• Surgery f/b Post-op RT/CT-RT
• Neoadjuvant chemotherapy f/b surgery
• Neoadjuvant chemotherapy f/b RT
• Radiotherapy with chemotherapy
• Radiotherapy with biological therapy

11. Pre-op RT followed by Surgery
• Indications
• Patients with fixed neck nodes.
• Emergency tracheostomy through tumor.
• Direct extension of tumor involving skin.
Perez & Brady's Principles and Practice of Radiation Oncology, chapter 47, p857

12. Surgery followed by Post-op RT
Indications
• Lymphovascular &/or Perineural invasion
• Multiple positive neck nodes
• Close or positive margins
• Extracapsular extension
• Significant subglottic extension (1cm or more)
• Cartilage invasion
• Endothelial-lined space invasion
• Soft tissue extension
• Control of subclinical disease in opposite neck.
Amdur RJ, Parson JT, Mandenhall WM et al. Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment
results and complications. Int J Radiat Oncol Biol Physics 1989;16(1):25-36.

13. • 354 patients with advanced H&N cancer randomized to 50 Gy
pre-op vs Post-op 60 Gy, 320 analyzed.
• At a median FU 60 months with a primary end point of
Locoregional control, post-op RT improved LRC at 4 years
(48% vs 65%, p = 0.04)
• For primaries of the supraglottic larynx (26% patients):
• LRC at 4 years 53% vs 77%
• OS at 4 years 41% vs 47%
• Complications not different
• PORT was shown to result in superior locoregional control (70%
vs. 58%) when compared to preoperative radiotherapy but did not
affect survival.
Preoperative RT Vs postoperative RT:
RTOG 73-03 (1987)
Kramer et al. Head Neck Surg, 1987.

14. Preoperative RT Vs postoperative RT:
RTOG 73-03 long term update (1991)
• The loco-regional control rates were
significantly better for the PORT patients
(70%) than for the Pre-Op RT patients (58%),
p = 0.04.
• Loco-regional failures constituted 59% of all
failures within 2 years in the PRE-OP RT
patient versus 55% for POST-OP RT. Beyond
2 years it was 27% versus 8%.
RTOG 73-03 Conclusion:
• Post op RT is the better approach for
management of resectable disease.
Tupchong et al. IJROBP 1991

15. Post-op RT alone Vs Post-op CTRT

16. Post-operative Chemoradiation
• In 2004, two major trials were reported (RTOG 95-01, Cooper
and EORTC 22931, Bernier) which evaluated post operative
CCRT against RT alone.
• Both found a better PFS in their CCRT arms; a combined analysis
was also done (Bernier, 2005).
• Conclusion: Patients with resected head and neck cancer with
positive margins or extranodal extension should be assigned to
combined chemoradiation approach using concurrent cisplatin.
1. Bernier et al. NEJM, 2004
2. Cooper et al. NEJM, 2004
3. Bernier et al. Head Neck, 2005

17. EORTC 22931 (Bernier et al) RTOG 9501 (Cooper et al)
N = 334 (167 to each arm, n = 75/334) N = 459 (231 RT, 228 CTRT, n = 86/416)
RT: 66 Gy/33# RT: 60 Gy/30#
Chemotherapy: CDDP 100mg/m2 on days 1, 22, 43 of RT
74% patients received all 3 cycles 61% received all 3 cycles
Median FU: 60 months Median FU: 45.9 months
HR for progression: 0.75
(95% CI 0.56 – 0.99, p = 0.04)
HR for recurrence/death: 0.78
(95% CI 0.61 – 0.99, p = 0.04)
OS: Significant benefit
HR 0.7, p = 0.02 (95% CI 0.52 – 0.95)
OS: Non significant benefit
HR 0.84, p = 0.19 (95% CI 0.65 – 1.09)
Combined analysis:
Inclusion criteria

18. On the basis of these trials, indications of CT-RT
Absolute Indications
• Margin +ve
• ECE +ve (in Node +ve)
Relative Indications
• LVE/PNI
• Close margins
• pT3 or more (Stage III or beyond)
• pN2a or more (Stage IV or beyond)
• Bulky nodal disease
• Lower neck LN
• The latter are generally taken as indications for RT alone.

19. Morbidity of Laryngectomy
• Loss of natural voice
• Altered deglutition
• Permanent stoma
• Pharyngocutaneous fistula (upto 30%)
• Stomal stenosis (25% - 40%)
• Aspiration (with partial laryngectomy, upto 40%)
1. Benito et al. Head Neck, 2011
2. Agrawal et al. Otolaryngol Clin North Am, 2008
3. Wax et al. Otolaryngol Head Neck Surg, 1995
4. Cousins et al. J Laryngol Otol, 1987

20. Radiotherapy approaches
• Definitive (Larynx Preservation)
• As a part of Combined modality treatment
• Alone
• With Concomittant chemotherapy
• NACT f.b. RT
• The biggest advantage with Radiotherapy as definitive
management is organ preservation.

21. Larynx Preservation
• Retrospective reviews: Posner (2009)
• Randomized Trials: VA trial (1991), RTOG 91-11 (2003),
GORTEC 2000-01 (2009), EORTC 24954 (2009),
TREMPLIN (2013)
• Meta-Analysis: MACH-NC (2000, 2006, 2009; subsite
analysis 2011)
Several studies have shown the effectiveness of Radiotherapy in definitive
management for disease that would otherwise need surgical resection. They
also studies with the question of the optimal chemotherapy regimen and
approach.

22. VA trial: Induction Chemotherapy and RT vs
Surgery and adjuvant RT (1991)
The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991; 324:1685-1690
• 332 patients with locally advanced (Stage III 188, IV 144) glottic
(124) and supraglottic (208) cancer were randomized into 2 arms:
Induction
Chemotherapy
2 cycles PF followed by
response assessment
At least PR
3rd cycle IC
then RT
< PR
Surgery +
PORT
Surgery + Post op Radiotherapy
versus
n = 166
n = 166
117/166
85%*
• 64% patients had biopsy confirmed CR after 3 cycles of PF.
• *14 patients in the Induction arm were taken up for RT after C2 NACT because of
toxicity or refusal for further chemotherapy.

23. Results
At a median follow up of 33 months:
• Larynx preservation: 107/166 patients (64%)
• No difference in OS at 2 years (68% each)
• Local recurrence was higher in IC group (12% vs 2%, p = 0.001)
• Distant mets (17% vs 11%, p = 0.001) and rate of 2nd primary (6% vs 2%, p =
0.048) were higher in the surgery group.
Overall Survival (months)Disease Free Survival (months)
Solid Line: IC
Dotted line: Surgery
Neither OS nor DFS
was significantly
different.
Conclusion
Induction chemotherapy followed by definitive RT is an effective
means of preserving the larynx without compromising overall survival.

24. RTOG 91-11: Randomized trial evaluating
Concurrent chemotherapy in Carcinoma Larynx
Forastiere et al. N Engl J Med. 2003;349(22):2091-8.
Radiotherapy alone (70Gy/35#)
Upfront chemoradioation (50-70 Gy)
Cisplatin [100 mg/m2] days 1,22 and 43
Induction Chemotherapy (PF, 2 cycles)
Cisplatin (100 mg/m2) d1
5-FU (1000 mg/m2/day) d1-d5
At least PR
3rd cycle IC
then RT
< PR
Surgery +
PORT
n = 173
n = 172
n = 173
• 547 patients with locally advanced (Stage III 337, IV 181) glottic (162) and
supraglottic (356) cancer randomized into 3 arms.
Exclusion criteria:
T1 or large volume T4
• Primary end point was larynx preservation, secondary end points were
OS, DFS, Laryngectomy Free Survival (LFS), Locoregional control (LRC).

25. Results Induction
(n=173)
Concurrent
(n=172)
Radiation
(n=173)
Laryngeal preservation (2 yrs) 75% 88% 70%
LFS (2 yrs) 59% 66% 53%
LFS (5 yrs) 43% 45% 38%
OS (2 yrs) 76% 74% 75%
LRC (2 years) 61% 78% 56%
Distant failures (5-year) 15% 12% 22%
Median FU
3.8 years
• Concurrent Chemoradiotherapy gave higher rates of larynx preservation than
Induction (p = 0.005) and RT alone (p < 0.001), and better LFS and LRC than
RT alone (p = 0.01, p < 0.001 respectively). Other comparisons, including OS,
were non significant.

26. Laryngeal preservation Locoregional Control
• Treatment failures were significantly fewer in the CRT [35] arm (p = 0.004 for
induction arm [61], p < 0.001 for RT alone[72]).
• Overall, patients who received chemotherapy had a better DFS than those who
didn’t (p = 0.02).
Conclusion
Concurrent chemoradiotherapy should be standard of care when
attempting laryngeal preservation in locally advanced disease.

27. RTOG 91-11 Long term results (2013)
• At a median follow up of 10.8 years, the advantage of CCRT over IC and RT
alone was maintained.
• However this was for end points other than DFS and OS.

28. LFS
OS
LRC
Laryngeal
preservation
• The authors concluded that similar LFS is afforded by both
chemotherapy based approaches (better than RT alone).
• The impact on OS and DFS still remains a subject of investigation.

29. EORTC 24954: Sequential vs Alternating
Chemotherapy & RT (2009)
• 450 patients with carcinoma larynx (218) and hypopharynx (231) and
predominantly Stage III (39%) or IV (58%) disease randomized to:
Lefebvre et al. J Natl Cancer Inst. 2009;101(3):142–152.
Alternating arm (n = 226)
4 cycles PF, Weeks 1,4,7 and 10
Alternated with 3 courses of RT (20Gy/10# each)
Sequential Arm (n = 224)
2 cycles PF followed by
response assessment
At least PR
2 more cycles
of induction PF
< PR
Surgery +
PORT
EBRT
70Gy/35#
versus
Primary end point:
• Survival with a
functional larynx
Secondary end points:
• DFS
• OS
• Larynx preservation
• QoL
• At a median FU of 6.5 years, no difference in OS,
PFS, or survival with a functional larynx. Toxicity
was also similar.

30. Choice of induction chemotherapy:
TPF vs PF

31. GORTEC 2000-01: Larynx preservation with TPF or PF
• 213 patients with larynx (98) or hypopharynx (115) cancers
with T2-T4, N0-N3 disease randomized to:
3 Cycles Induction
Chemotherapy followed
by response assessment
At least PR
RT
(optional 4th IC)
< PR
Surgery +
PORT
TPF
PF
n = 110
n = 103
N = 213
• Primary end point: 3 year-laryngeal preservation rate
• Secondary end points:
• Overall survival
• Response rate to ICT
• DFS
• Acute and late toxicity rates
Pointreau et al. J Natl Cancer Inst. 2009;101(7):498-506.

32. • The overall response rate after induction chemotherapy was 80.0% (41.8%
complete response and 38.2% partial response) in the TPF group and 59.2%
(30.1% complete response and 29.1% partial response) in the PF group
(difference = 20.8%; P = .002).
RT: 84/106 RT: 57/100

33. Median FU of 36 months:
• 3-year LPR 70.3% in TPF arm and 57.5% in
PF arm. (p = 0.03).
• 3 year OS was the same in both arms (60%).
• 3 year DFS was better with TPF but failed to
reach statistical significance (58% vs 44%, p
= 0.11).
DFS
Larynx preservation
Overall Survival

34. GORTEC 2000-01: Larynx preservation with TPF or PF
Long term update (2016)
Janoray et al. J Natl Cancer Inst. 2016;108(4).
Median FU
105 months
5 years 10 years
TPF PF TPF PF
Larynx
Preservation
74% 58.1% 70.3% 46.5%
LDFFS 67.2% 46.5% 63.7% 37.2%
OS 50.9% 41.9% 30.2% 23.5%
DFS 42.4% 31.4% 25% 18.7%
LRC 46.6% 36.3% 27.9% 20.8%
• Differences observed in
Larynx Preservation and
Larynx dysfunction free
survival (LDFFS) were
statistically significant.
• The authors noted that the
study was underpowered to
detect a difference in OS,
DFS and LRC.
Conclusion: The TPF regimen was superior to the PF regimen in terms of
organ preservation and preservation of functionality of the larynx. Therefore
when NACT → RT is given, TPF should be the preferred regimen.

35. Sequential therapy for the locally advanced larynx
and hypopharynx cancer subgroup in TAX 324
• A retrospective subgroup analysis of TAX 324
• 166 patients (90 TPF, 76 PF) with carcinoma larynx (89) and
hypopharynx (77). However, only 123/166 had resectable disease (67
TPF, 56 PF).
Posner et al. Ann Oncol. 2009;20(5):921-7.
• LFS was significantly improved with TPF compared with PF (HR: 0.59; 95% CI
0.37–0.95; p = 0.030)

36. 2013: TREMPLIN
Induction chemotherapy followed by either
chemoradiotherapy or Bioradiotherapy
3 Cycles Induction
Chemotherapy followed
by response assessment
CDDP
Cetuximab
EBRT
70Gy/35#
N = 153
> PR
n = 116
• Stage III (65) and IV (38) patients of carcinoma hypopharynx (69) and larynx
(47) were randomized for a Phase II study.
n = 60
n = 56
Primary end point
• LP rate at 3 months post-treatment (95% vs 93%, NS)
Secondary end points
• Larynx function preservation (LFP) at 18 months (87% vs 82%, NS)
• Overall Survival (92% vs 89%, NS)
• Tolerance and compliance with treatment
Median FU
36 months
Conclusion: Bioradiotherapy can be considered as a substitute for Cisplatin based CCRT.

37. MACH NC Meta-analysis
• 1st publication1 (2000): Over 70 trials that randomized >10,000 patients.
• Update #12 (2007): 87 trials, 16665 patients, median f/u 5.5 years.
• Update #23 (2009): 93 trials, 17,346 patients, median f/5 5.6 years.
• Three comparisons
1. The effect of chemotherapy: LR treatment was compared with LR
treatment plus chemotherapy.
2. The timing of chemotherapy: NACT plus radiotherapy was compared with
concomitant or alternating Radio-Chemotherapy with the same drugs.
3. Larynx preservation with neoadjuvant chemotherapy: Radical surgery plus
RT was compared with NACT + RT in responders or radical surgery and
radiotherapy in non-responders.
1. Pignon et al, Lancet 2000; 355: 949–55
2. Pignon et al. Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S112-4.
3. Pignon et al. Radiother Oncol. 2009;92(1):4-14.

38. • 87 randomised control trials from period of 1965 to 2000
• 16,485 patients were analysed with a median follow up 5.6 years
• Absolute benefits
- Oral cavity: 8.9%
- Oropharynx: 8.1%
- Larynx:5.4%
- Hypopharynx: 4%
Larynx
• 3216 patients with laryngeal cancer and 61 comparisons included.
• The HR of death associated with chemotherapy was 0.87 (95% CI: 0.80–0.96),
corresponding to an absolute 5-year OS benefit of 4.5% (95% CI: 0.8–8.2),
increasing from 42.5% to 47.0%.
• Apart from chemotherapy timing, no analysed subset or subgroup characteristic had
a significant interaction with chemotherapy benefit.
MACH-NC: Analysis by subsite (2011)
Blanchard et al. Radiother Oncol. 2011 Jul;100(1):33-40.

39. MACH- NC-Conclusions
• Addition of CT - Absolute survival benefit of 5% at 5 yrs.
- Induction/adjuvant: 2%
- Concurrent: 8%
• Platinum based regimen more effective.
• No significant difference in efficacy between mono and multiple
drug platinum regimens
• Small reduction in distant metastasis found in population of
patients with CTRT.
• Inverse relation between age and impact of chemotherapy that
disappears by around age of 70.

40. Chemotherapy: Summary
• Addition of chemotherapy to definitive radiotherapy is an
effective means of laryngeal preservation without
compromising survivals.
• The benefit is more with concurrent than with Neoadjuvant
chemotherapy.
• While the MACH-NC analyses suggest a survival advantage,
individual head-to-head trials have failed to show this benefit.

41. Altered Fractionation
Evidence
• Retrospective reviews: Lee (1997), Garden (2003)
• Randomized Trials: RTOG 90-03 (2000), Overgaard (2003),
Yamazaki (2006), RTOG 95-12 (2014)
• Meta-Analysis: MARCH (2006)

42. Lee et al (1997): Influence of fraction size, total
dose, and overall time on local control of T1–T2
glottic carcinoma
Quynh-Thu X. Le, Karen K. Fu, Steward Kroll, et al. International Journal of Radiation Oncology*Biology*Physics, Volume 39, Issue 1,
1 August 1997, Pages 115-126
• Retrospectively reviewed 398 patients (315 T1 and 83 T2 Glottic Cancers)
treated with RT alone.
• The fraction sizes were:
• For T1 lesions, within the dose and time range evaluated, there was no
apparent relationship between fraction size, overall time, total dose, and
local control on multivariate analysis.
 Improved local control for T2 lesion as compare to T1 lesion (85% vs 70%).
 100% for fraction size ≥2.25 Gy vs. 44% for fraction size <1.8 Gy. (p = 0.003),
 78% for total dose >65 Gy vs. 60% for total dose ≤65 Gy. (p 0.01)
 58% for lesions with sub glottic extension vs. 77% for those without (p 0.04).
<1.8 Gy in 146 1.8-1.99 Gy in 128 2.0-2.24 Gy in 62 ≥2.25 Gy in 62

43. Garden et al (2003): Results of Radiotherapy for
T2N0 Glottic carcinoma. Does the “2” stand for twice
daily treatment?
• Reviewed 230 patients of T2 glottic cancer treated with RT alone
• 3 different fractionation schedules
• Conventional: ≤2 Gy/fraction; Once daily treatment (89 pts.)
• Accelerated: >2Gy/fraction; Once daily treatment (57 pts.)
• Hyperfractionation : 1.1-1.2 Gy/fraction; Twice daily
treatment. (83 pts.)
• 5-year local control
• Twice daily fractionation: 79%
• Once daily fractionation: 68%
• Once daily with doses > 2 Gy: 82%.
• Subglottic extension: 63%; No subglottic extension: 81%
Garden AS et al. Int. J Radiation Oncology Biol Phys, vol 55, No. 2, pp 322-328,2003.

44. RTOG 90-03 (2000): Phase III Study of Altered
fractionation vs Standard Fractionation
• Patients with stage III or IV SCC (n=1076) were randomized to 4 arms with 2
year LRC being the primary end point.
• 173/1076 (16%) patients of Supraglottic larynx
• Median follow up – 23 months
• HFX (p=0.045) & AFX-C (p=0.05) improved LRC
• Trend towards improvement in DFS for both HFX & AFX-C
• No significant difference in OS
Int J Radiat Oncol Biol Phys, 2000 Aug 1;48(1):7-16.

45. RTO 90-03 Results
TOXICITY:
Altered fractionation regimens
were associated with higher
incidence of grade 3 or worse
acute mucosal toxicity, but no
significant difference in overall
toxicity at 2 years following
completion of treatment.
2 yr LRC 2 year DFS 2 yr OS
Standard
Fractionation
46% 31.7% 46.1%
Split course
Accelerated
47.5% 33.2% 46.2%
Concomitant Boost 54.5%
(p = 0.05)
39.3%
(p = 0.054)
50.9%
Hyperfractionated 54.4%
(p =
0.045)
37.6%
([p = 0.067)
46.1%
Updated results: 2014 (Beitler et al, IJROBP 2014)
• When censored at 5 yrs for LRC,
• Only HFX showed significant improvement ( p - 0.05)
• HFX improved overall survival (HR 0.81, P=.05)
• DFS was improved for all 3 arms (non-significant)

46. • To assess if shortening the OTT by pure acceleration (6#/wk) improves the
tumour response compared to standard fractionation
• 1476 patients of glottic (690), supraglottic (218) and other sites (568) with
29%, 25%, 21% and 25% Stage I, II, III and IV disease.
• Comprising two subprotocols:
DAHANCA 6, which included all glottic carcinomas, and
DAHANCA 7, which included the rest.
• Primary end point: LRC
• Secondary end points:
- Local T site and regional N site control
- Voice preservation
- Disease-specific survival
- Overall survival
- Treatment morbidity
DAHANCA 6 & 7 (2003): Five vs Six fractions a
week in Head and Neck Cancer
Overgaard et al. Lancet. 2003 Sep 20;362(9388):933-40.

47. 5-year LRC: 70% vs 60%
for 6# vs 5#, p=0.0005
Primary tumour control: 76
vs 64% for 6# vs 5#, p=0.0001
Disease-specific Survival: 73
vs 66% for 6# vs 5#, p = 0.01
OS was similar; HR 0.98
(95% CI 0.8 – 1.21, p = 0.78

48. Yamazaki et al (2006): Randomized trial in
T1N0M0 glottic Carcinoma
Int J Radiat Oncol Biol Phys. 2006;64(1):77-82
ARM Tumor <2/3 of glottis
(minimal disease)
Tumor >2/3 of glottis
(> minimal disease)
A1 (n=31) 60 Gy/30#/6 wks
A2 (n=57) 66 Gy/33#/6.5 wks
B1 (n=31) 56.25 Gy/25#/5 wks
B2 (n=61) 63 Gy/28#/5.6 wks
N = 180
Results
• The 5-year local control rate for the entire group was 86%
• 76% for Arm A vs 92% for Arm B (p = 0.004)
• Treatment toxicity was not significantly different between the two arms.

49. Conclusion
• The 2.25-Gy/fraction scheme with a shorter overall treatment
time is superior to 2 Gy/fraction for local control of Stage T1
glottic carcinoma.
• No difference was found between the two arms in terms of
OS (87% for Arm A, 88% for Arm B) or cause specific
survival (98% for Arm A and 100% for Arm B).
Yamazaki et al. Int J Radiat Oncol Biol Phys. 2006;64(1):77-82

50. RTOG 95-12 (Trotti, 2014): Randomized trial in T2
Glottic Carcinoma
Int J Radiat Oncol Biol Phys. 2014;89(5):958-63.
• 250 patients, randomized into
• Standard Fractionation Arm (SFX)
70Gy / 35# (2Gy/#, once daily, 5 days/wk, 7 wks)
• Hyperfractionation Arm (HFX)
79.2Gy / 66# (1.2Gy/#, twice a day, 5 days/wk, 6.5 weeks)
Results
• Similar Grade 1 and 2 acute toxicities in both arms
• Higher acute grade 3 toxicity with HFX than with SFX (33.3% vs 22.7%;
p=0.084), but no difference in late grade 3 toxicity at 5 years (8.5% in both
arms).
• Primary end point: Local control at 5 years was 70% vs 78%, p = 0.14.
• Locoregional control was 67% vs 73% (HR 0.77, p = 0.26).

51. Conclusion
• The 5-year local control was modestly higher with HFX compared to SFX
for T2 glottic carcinoma, but the difference was not statistically significant.
5 year local control
Trotti et al. Int J Radiat Oncol Biol Phys. 2014;89(5):958-63.

52. • 15 Randomized Trials of Varied Fractionation with 6515 patients (1970-1998)
• Mostly Oropharynx (44%) and Larynx (34%) patients
• Follow up from 4 to 10 years, median 6 years
• 74% stage III & IV disease
Overall Hyper-
fractionation
Accelerated
fractionation, same
total dose
Accelerated
fractionation, total
dose reduced
OS
Benefit
3.4% 8.2% 2% 1.7%
LRC
Benefit
6.4% 9.4% 7.3% 2.3%
• Overall, 8% reduction in risk of death
• Survival benefit at 2 years – 3.3% , at 5 yrs – 3.4 %
MARCH Meta-analysis (2006): Hyperfractionated or
accelerated radiotherapy

53. Survival curves by treatment arm for all trials and according to the type of altered fractionated radiotherapy
(A) Hyperfractionation. (B) Accelerated fractionation without total dose reduction. (C) Accelerated fractionation with total dose reduction. (D) All three groups
together. The slopes of the broken lines from year 6 to year +7 are based on the overall death rates in the seventh and subsequent years
Hyperfractionation
Accelerated RT without
dose reduction
Accelerated RT with
dose reduction
A, B and C
combined

54. Locoregional control curve by treatment arm according to the type of radiotherapy(A) Hyperfractionation. (B) Accelerated
fractionation without total dose reduction. (C) Accelerated fractionation with total dose reduction. (D) All three groups together.
Hyperfractionation
Accelerated RT without
dose reduction
Accelerated RT with
dose reduction
A, B and C
combined

55. Altered Fractionation: Summary
• In early Glottic Carcinoma, reducing the overall treatment time
(OTT) provides good disease control and hypofractionated RT
can be considered for this purpose. (Yamazaki, DAHANCA 6&7)
• In locally advanced disease, conventional fractionation is still the
norm though there is benefit from reduction in OTT by
acceleration or hypofractionation (MARCH meta-analysis).
• Hyperfractionation is a valid option, but its adoption in a resource
strained setting is difficult. (RTOG 90-03, MARCH)

56. Other major studies
Induction Chemotherapy
• TAX 323 (2007) and 324 (2007, upd 2011), PARADIGM (2013),
DeCIDE (2014)
Concurrent chemo/biological therapy
• Jeremic et al (1997), Wendt et al (1998), Adelstein et al (2000
and 2003)
• Bonner et al (2006, upd 2010), RTOG 0522 (2014)
Altered fractionation
• Brizel et al (1998), Jeremic et al (2000), RTOG 0129 (2014)

57. Other major trials: Concurrent chemo/biological therapy
Jeremic et al (1997)
n = 28/159
CTRT (low dose daily
Cisplatin or carboplatin) vs
RT alone
CTRT: better than RT alone
Wendt et al (1998)
n = 97/270
CTRT (PF) vs RT alone
(split course RT with 2 breaks)
CTRT: better than RT alone
Adelstein et al
(2000) n = 52/118
CTRT (PF) vs RT alone
(RT given: SFX upto 72 Gy)
CTRT: better local control, but
not OS
Adelstein et al
(2003) n = 75/271
CTRT (SFX and Split
course) vs RT alone (SFX
only): 3 Arm study
CTRT-SFX superior to both
other arms
Bonner et al (2006,
2010) n = 163/424
RT + Cetuximab vs RT alone Bioradiotherapy is superior to
RT alone.
RTOG 0522 (2014)
n = 266/891
Cisplatin with AFX-RT with
or without Cetuximab
No benefit from addition of
Cetuximab

58. Other major trials: Altered Fractionation
Brizel et al
(1998)
n = 18/116
Accelerated hyperfractionation (A-
HFX) vs CCRT in SFX
SFX-CCRT is more
efficacious, and not more
toxic.
Jeremic et al
(2000)
HFX-RT with or without daily
concurrent low dose cisplatin
Concurrent CDDP gave
significant OS benefit.
RTOG 0129
(2014)
Concurrent CDDP: AFX-C vs SFX AFX doesn’t improve
outcome if concurrent Chemo
is given.
Other major trials: Induction Chemotherapy
TAX 323 (2007)
n = 130/321
TPF vs PF as NACT, followed by RT
alone
TPF gave better OS
and DFS
TAX 324 (2007)
n = 166/501
TPF vs PF as NACT, followed by CCRT
(carboplatin)
TPF gave better OS
than PF.
PARADIGM
(2013) n = 39/145
NACT followed by CCRT vs upfront
CCRT
IC doesn’t improve
survival.
DeCIDE (2014)
n = 37/273
NACT followed by CCRT vs upfront
CCRT
No difference in OS

59. Site & Stage 5 Yr. LRC OS Cause Specific Survival
Early stage
Glottic cancer
Stage I : 85-95%
Stage II:70- 80%
75-90% 90-100%
Early stage
Supraglottic
cancer
Stage I :100%
Stage II:85%
60-65% 90-100%
Results of Definitive Radiation Therapy
Mendenhall et al. Cancer, 2004
Hinerman et al. Head Neck, 2002
• Early stage disease
Site & Stage 5 Yr. LRC OS 5 Yr DFS
Advanced stage
larynx cancer
35-75% 25-55% 25-45%
• Advanced disease
Fu et al. 2000; Forastiere et al. 2003; Bonner et
al. 2006; Adelstein et al.2003; Brizel et al.1998).

60. Summary
• Radiotherapy is an effective means of larynx preservation
without compromising survivals.
• Addition of chemotherapy provides better results for larynx
preservation than RT alone (concurrent > NACT). However
the impact on survival is still unclear.
• Specifically for early glottic cancers, hypofractionated RT
can provide better outcomes.

61. Radiation Therapy
• Pre treatment prophylaxis
• Technique
• Dose & fractionation
• Post treatment follow up
• Side effects

62. Pre-treatment Prophylaxis
• Dental prophylaxis:
• Extraction
• Scaling
• Repair of sharp edged teeth
• Application of fluoride gel
64

63. RTP Technique
• CT-based planning is recommended
• Laryngeal primaries typically treated with lower energy beams, Co-
60 or Linear Accelerator (4 MV – 6 MV photons).
• Position: supine with rigid head holder cradling the posterior
calvarium.
• Shoulders should be positioned as caudally as possible to allow
adequate exposure of neck.
• Head should be immobilised with a thermoplastic cast.
• Anterior and Lateral reference marks should be made on the mould
• Bite block may be used to elevate the hard palate
• Image should be taken from above the calvarium to the carina.

64. Radiation therapy - simulation
Head Rest - Timo Thermoplastic Mask
Shoulder Retractor
Especially when LAN fields not to
be used, to maximize coverage
with lateral fields.

65. Conventional radiotherapy

66. Radiotherapy for early glottic cancer
(Tis/T1/T2;N0)

67. Conventional: 2 Field Technique
• Typically delivered by small portals covering only the primary lesion;
cervical node are electively not treated.
• 5×5 or 6x6 cm opposed lateral fields
• Wedges/compensators for tissue deficit due to neck anatomy may be
required.
• Bolus may be needed for anterior commissure tumors and over the
tracheostoma (if present)
 Randomized study comparing 5×5 cm to 6×6 cm fields showed that 5 × 5 cm
is associated with less arytenoid edema with identical year recurrence free
survivals.1
1. Chatani et al. Strahlenther Onkol, 1996

68. Superior border: Top of the thyroid notch
Inferior border: bottom of the cricoid
cartilage
Anterior border:1 cm flush of skin at the
level of thyroid cartilage
Posterior border: Ant. edge of vertebral
bodies
Fields For Tis/T1 Glottis Carcinoma
For T1N0, use a 5 × 5-cm field

69. RT Fields For T2 Glottic Cancer
: depend on degree of Supraglottic /subglottic extension
• Field size increased to 6×6 cm opposed lateral fields
• Larger fields covering level II-III L.N (2-7% risk of nodal involvement)
Superior border: adjusted according to the lesion.
• Early lesion: middle of the thyroid notch
• Larger lesions: top of the thyroid notch
Inferior border :
• No subglottic extension: Bottom of the cricoid cartilage
• Subglottic extension: Border lowered up to 1 tracheal ring
Anterior border:
• 1 cm flush of skin at the level of thyroid cartilage
Posterior border:
• Ant. 2/3 of V.C: ant. edge of vertebral bodies
• Posterior 1/3 V.C involved: at middle of vertebral bodies

71. Glottic larynx traditional field design.
Lateral portal showing a field used
to treat a T1 glottic carcinoma
• Wedges can be removed to add hotspot
in anterior region with an anterior
bolus.
• For anteriorly placed tumours without
involvement of the posterior vocal cord,
posterior border can be moved
anteriorly by 0.5 cm after a dose
sufficient for subclinical disease
(approximately 50 Gy for standard
fractionation) is achieved.
- To reduce arytenoid edema

73. Technique for early glottis carcinoma: 3 field
technique
• ~90 - 95% dose is delivered through opposed lateral wedged
fields weighted to the side of the lesion
• Remaining dose is delivered by an anterior field shifted 0.5 cm
toward the side of the lesion
• In such cases, dose is usually specified at the 95% normalized
isodose line.
Normalized isodose distribution for three-field
technique for treatment of a tumor involving
the anterior two-thirds of one true vocal cord.
The dose is specified at the 95% isodose line.

74. T1 Glottic Cancer
• Conventional Fractionation: 66 Gy in 33# @ 2 Gy/#
• Hypofractionation1: 2.25Gy/# ;
- 63 Gy/28 fr/5.6 wk
- 56.25Gy for Cis
• Smaller daily fractions should not be used as studies have suggested that
they are associated with reduced local control rates.2,3
Dose and Schedules
1. Yamazaki et al. IJROBP 2006
2. Mendenhall et al, Cancer 2004
3. Mendenhall et al, IJROBP 1988

75. • Conventional Fractionation
70 Gy/ 35#/7 weeks @ 2 Gy/#
If level II-III nodes included 54 Gy to larger field with smaller field covering
larynx only upto 70 Gy
• Hypofractionation
65.25Gy/29# @2.25Gy/#
• Hyperfractionated
79.2 Gy/ 66 #/6.5 weeks @ 1.2Gy/# bid)
- May provide better sidease control
- No prospective evidence-based data
1. Garden et al, IJROBP 2003
2. Yamazaki et al, IJROBP 2006
3. RTOG 95-12, IJROBP 2014
Dose and Schedules
T2 Glottic Cancer

76. Radiotherapy for early supraglottic cancer

77. General Principles
• 20-50% of T1-T2 Supraglottic cancer have +L.N so objective is to
cover both the primary and clinical/subclinical disease in the
Levels II and III cervical nodal beds.
• Shrinking field technique with off cord + GTV boost (2 or 3
phases)
• For extensive supraglottic disease 3 Field technique used
- 2 lateral field + matched LAN field to cover the low anterior
nodes (i.e. levels I - IV)
• Gross nodal disease in the post neck to be bossted with 6–9 MeV
electrons after off cord done at 45Gy.

78. Low anterior neck field
• Superiorly: Match with the inferior
borders lateral field
• Laterally: at junction of medial
2/3rd and lateral 1/3rd of clavicle
• Inferiorly: 1cm below clavicle

79. Initial treatment portals:
Lateral opposed fields
Off spinal cord lateral fields Post. neck boosted with
matched electron-beam
Final boost fields to the
tumor with a margin.
SCF field matched to the upper
neck (lateral) fields

80. Radiation therapy for locally advanced laryngeal
cancer

83. Dose and Schedules
Standard fractionation:
- 70 Gy in 35 fractions over 7 weeks to gross disease
- 50 Gy to subclinical disease.
Altered fractionation:
- Hyper fractionated:76.8 Gy/1.2Gy/#
- Concomitant boost :72 Gy/42 fractions/6weeks
54 Gy/30#/6weeks @ 1.8 Gy/#/day to larger field
1.5 Gy/#/day boost field given 6hrs later for the last 12 treatment days

84. Radiotherapy for advanced larynx cancer

85. Field design for locally advanced disease
Anterior border:
• Allowed to fall off, entire pre-epiglottic space
included
Posterior border
• Behind the vertebral spinous process (typically
C1 or C2, more posteriorly in presence of large
nodal mass)
Inferior border
• If no subglottic spread: Bottom of cricoid
cartilage in the presence of subglottic extension,
2 cm below lower extent
Superior border:
• 2cm above the angle of mandible if N0
• 1cm above tip of mastoid if N+
• May extend upto base of skull to cover retropharyngeal L.N

86. • Conventional treatment involves a shrinking field technique; 3 field
- 2 parallel opposed lateral field encompassing the primary tumor
and upper neck lymphatics
- Low anterior neck field:to include level IV L.N
- Match the lateral fields to the low-neck AP field.
Field design for locally advanced disease

87. Standard Fractionation
- Gross disease :70 Gy/35#/7 weeks @ 2 Gy/#/day
- Subclinical disease: 50 Gy@2 Gy/#/day
Concomitant Boost Radiotherapy Therapy
- Total dose:72.0 Gy/42 # over 6 weeks as 54 Gy in 30 # (1.8 Gy/#/day) to a
relatively large field including subclinical disease
- A second daily fraction at least 6h later 18.0 Gy/12# (1.5 Gy/#) to a small “boost
field” for gross disease
Hyperfractionation
- 81.6 Gy in 7 weeks at 1.2 Gy b.i.d.
Dose and Schedules

88. 3D Conformal Radiotherapy

89. Delineation
• Gross tumor volumes (GTV) – includes all known primary and cervical lymph
node tumor extension based on clinical, endoscopic and imaging findings.
• Clinical target volume (CTV) –
• HRCTV: GTV is expanded to include a margin for microscopic extension forming
high dose CTV.
• LRCTV: nodal regions at low risk for occult submicroscopic spread included in a
low-risk CTV.
• IRCTV: optional. Includes area adjacent to GTV at high risk of having occult
submicroscopic spread
• Planning target volume (PTV): CTV is expanded with 3-7 mm margin to account
for organ motion & setup error

90. Determination of CTV
• Based on the incidence & location of metastatic node
from larynx primary

91. Chao et al. IJROBP, 2002

92. CTV Determination
Tumor site Clinical Stage CTV1 CTV2 CTV3
GLOTTIC T1-T2 N0 GTVp - -
T3-T4 N0 GTVp Optional I/L +C/L II-V
anyT N+ GTVp+N I/L adjacent
L.Ns
I/L+C/L
(remaining L.N)
± RPLN
SUPRA-
GLOTTIC
Any T N0 GTVp Optional I/L+C/L II-V
Any T N+ GTVp + N I/L adjacent
L.Ns
I/L+C/L
(remaining L.N)
± RPLN
*Practical Essentials Of IMRT; KS Clifford Chao

93. Pre-op RT followed by Surgery
• Indications
• Patients with fixed neck nodes.
• Emergency tracheostomy through tumor.
• Direct extension of tumor involving skin.
• The treatment technique is same as that of RT alone
• Lower dose: 50 - 60 Gy@1.8- 2.0 Gy/# to entire target
• Boost dose: 66-70Gy to areas of unresectable disease (usually the neck)
Perez & Brady's Principles and Practice of RadiationOncology, chapter 47, p857

94. Post-op RT
• Conventional 2-3 field technique
• Lateral fields cover tumor bed, neopharynx, adenopathy and 1.5–
2 cm margin on preoperative extent of disease
• Stoma is included in LAN field (with a subsequent boost if
indicated)
• Emergent tracheostomy
• Subglottic extension,
• Tumor invasion to soft tissues of neck,
• Extranodal extension in level VI,
• Close/+ margin,
• Scar crosses stoma

95. Post-op RT: dose & fractionation
• The dose for postoperative RT as a function of known residual
disease is as follows:
• negative margins, 60 Gy/ 30 #
• microscopically positive margins, 66 Gy /33#
• gross residual disease, 70 Gy/35#
• The lower neck (including stoma) is treated with doses to 50
Gy/25#. Stoma to be boosted upto 66 Gy if indicated.
• If there is subglottic extension, the dose to the stoma is boosted
with electrons usually 10 to 14 MeV electron for an additional
10 Gy/5#.
• If postoperative RT is added after supraglottic laryngectomy, the
dose may be lowered to 55.8 Gy given in 1.8-Gy fractions.

96. • The most common indications for IMRT for laryngeal cancers would be
patients with a node-positive T3–T4 cancer, where the retropharyngeal
nodes would be electively irradiated.
• Extensive subglottic invasion, where achieving an difficult to achieve
adequate inferior margin with conventional lateral portals.
• Advantages:
• Dose to the contralateral parotid gland can be reduced
• Can circumvent a difficult low match between the lateral fields and the
LAN field in a patient with a short neck and large shoulders.
• Carotid sparing IMRT only in selected cases
Role Of IMRT In Laryngeal Cancer
• IMRT is not recommended for T1–2, N0 glottic cancers, but may be
considered for more advanced lesions

97. Fractionation schedule in IMRT
Simultaneous integrated boost (SIB)
• in 35#: GTV = 70Gy/35#, CTV1 = 63Gy @ 1.8Gy/#, CTV2 = 56 Gy @ 1.6Gy/#.
• In 33#: GTV = 70Gy/33# @ 2.12Gy/#, CTV1 = 59.4 Gy @ 1.8Gy/#, CTV2 =
54Gy at 1.64Gy/#.
Sequential (2 or 3 phase planning)
• Initial lower-dose phase (weeks 1–5) followed by high dose boost volume phase
(weeks 6 and 7) using 2-3 separate dose plans.
Concomitant Boost schedule.
• Delivers dose to subclinical targets once daily for 6 weeks, and a separate boost
plan as second daily treatment during last 12 treatment days.

98. Dose limitations
• Spinal cord maximum dose <45–50 Gy.
• Brainstem maximum dose <54 Gy.
• 50% of the volume of each parotid <20 Gy and mean dose <26 Gy.
• Mandible maximum dose <70 Gy.
• Brachial plexus dose <60 Gy.
*WL: Whole Larynx, SVCI: Single Vocal Cord Irradiation

99. Post-Treatment Follow-Up
• Follow-up is important because early detection of recurrence
results in salvage that may include cure with voice
preservation.
• The majority of recurrences will occur within the first 2
years and nearly all within 3 years (Fu et al. 2000; Forastiere
et al. 2003, 2013).
• Patients are followed 1-2 monthly for the 1st year, 2-4
monthly for the 2nd year, 3-6 monthly for years 3-5 and
annually thereafter.

100. Work-Up at each follow up
• History/physical examination
• endoscopy or indirect mirror exam.
• Imaging of the neck (whenever patients develop new signs
or symptoms suggestive of recurrence)
• Imaging of the thorax recommended annually.
• TSH every 6–12 month if neck irradiated.
• Speech, swallow, dental, and hearing evaluations and
rehabilitation as indicated.
• Smoking cessation counselling.

101. Acute Effects
• Hoarseness
• Sore throat
• Dysphagia
• Odynophagia
• Mucositis
• Skin pigmentation in radiation field
• During RT or within 90 days of start of RT

102. Late reactions
• Develop/persist more than 90 days after start of RT
• Laryngeal oedema
• Glottic stenosis
• Xerostomia
• Swallowing dysfunction
• Pharyngeal stricture
• Weight Loss
• hypothyroidism