1. The International Federation
of Head and Neck Oncologic Societies
Current Concepts in Head and Neck Surgery and Oncology 2012
Radiation Therapy for
Laryngeal Function Preservation
Brian O Sullivan
1

2. Controversy has Characterised the Literature of
Laryngeal Cancer for Decades
Controversies even greater in early disease (endoscopic vs RT especially)
Preference for Surgery in T3N0 Preference for Total Laryngectomy
glottis
2012

3. Histology
>95% SCC
– Variations :
• verrucous carcinoma, spindle cell
carcinoma, basaloid SCC, and
papillary SCC
• hyperplasia, dysplasia, CIS
2012

4. 2012

5. Radiotherapy is a Staple among Organ-preservation strategies
2012
Available online at http://www.asco.org/guidelines/larynx

6. Does Increasing Use of Radiotherapy Over 3
Decades Worsen the Outcome for Laryngeal
Cancer ?
“A Population-Based Study of 13,808 US Patients”
• Radiotherapy with its advantage of organ preservation
has been used to treat laryngeal cancer (LC) for
several decades.
• Authors studied 3 periods:
– 1988 - 1993, 1994 - 1999, 2000 – 2006
• Conclusion: No negative impact of radiotherapy on
cancer survival of glottic or supraglottic larynx cancer
2012
Zhang, H., Travis, L. B., Chen, R., et al
Cancer 118 (5) 1276–1287, 1 March 2012

7. 2012

8. General Philosophy of laryngeal preservation
in management of laryngeal cancer
• Major local modalities:
– Surgery and/or radiotherapy
• Treatment choice depends on:
– stage, and tumor volume and extension
– laryngeal tumor location: anterior commissure
and subglottic involvement
– Patient factors: co-morbidity, smoking, male
gender, and anemia
– likelihood of functional preservation,
– patient preference
2012

9. Regional Spread in Laryngeal Cancer
• Except for glottic T1, and some early T2s
• Regional lymph nodes must be accounted for:
– Midline nature – bilateral involvement is possible and treatment
must address
– Levels II, III, IV are at risk
– Risk is increased by size, stage, supraglottic, tumor differentiation
• Influences the radiation volumes used
• Meticulous attention to post treatment imaging 8-12 weeks
after completion of radiotherapy is essential to safeguard
against uncontrolled disease that may be avoided by neck
2012
dissection.

10. Distinct Issues About Radiotherapy for
Laryngeal Cancer
• Bilateral radiotherapy for all except T1 Glottic
• Bulky T4b is generally best managed by surgery
and post-operative RT +/- concurrent
chemotherapy
• All other disease settings should be presented the
option of organ preservation using a radiotherapy
2012
strategy (alone or with concurrent chemotherapy)

11. 2012

12. 2012

13. Treatment – Early Stage (I/II)
• Current therapeutic options
– Laser microsurgery (transoral)
– Open partial laryngectomy
– Radiation therapy
• No RCT to compare surgery w/XRT
• Rate of local control similar between surgery
and radiation
• Current recommendations: XRT with surgery
reserved for salvage therapy with local
2012 recurrence
Mendenhall WM et al., Cancer. 2004 May 1;100(9)

14. Randomized
trials
recommended to
resolve these
controversies:
Need to consider
the challenges in
a disease with so
few events.
2012

15. Radiotherapy of T1 Glottic Cancer (1)
• Traditionally one of the most straightforward
techniques in radiation oncology
– Small volume
– Reproducible anatomy
– Regional nodes do not need to be considered
• Emerging evidence that IMRT with contralateral
carotid preservation may be possible
2012

16. Radiotherapy of T1 Glottic Cancer (2)
• Irrespective of the technique
– Movement of larynx (superior and inferior respiratory
motion and internal vocal cord) warrant caution in changing
targets
– Anterior commissure disease warrants attention to
dosimetric coverage to minimize geographic miss (usually
requires tissue isodense bolus placed)
– Dose needs to be adequate and of adequate fraction size
(single daily fraction sizes of 1.8 should be avoided in favor
2012 of larger dose per fraction, or altered fractionation)

17. T1 and T2 Glottic University of Florida 5
Year Radiotherapy Results
Initial Ultimate Ultimate
Local Local LC + Larynx Stage
N Control % Control % Preserved %
T1a 230 94 98 95
T1b 61 93 98 98
T2a 146 80 96 82
T2b 82 72 96 76
2012
Mendenhall WM et al JCO 2001: 19:4029-4036

18. T1 and T2 Glottic University of Florida
5 year Radiotherapy Results
Absolute Cause specific
Survival % Survival %
T1a 230 82 98
T1b 61 79 98
T2a 146 77 95
T2b 82 77 90
2012
Mendenhall WM et al JCO 2001: 19:4029-4036

19. Dose Fractionation in Early Disease
• Yu et al., 1997 [1]
– Retrospective study – 5 yr local ctr rate of XRT on T1
glottic CA
– Daily fx > 2 Gy (50 Gy/2.5Gy QD & 65.25Gy/2.25 Gy QD)
had 5 yr local ctr rate of 84%
– Daily fx = 2 Gy had 5 yr local ctr 65.6%
• Yamazaki et al., 2006 [2]
– RTC – in T1 glottic CA addressing dose per fraction
• Andy Trotti et al, RTOG 95-12 – closed [3]
– Randomized pts with T2 glottic cancer to 70Gy/2Gy QD vs
79.2 Gy/1.2 Gy BID
2012
1 Yu E. et al., Int J Radiat Oncol Biol Phys. 1997 Feb 1;37(3):587-91
2 Yamazaki H et al., Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):77-82
3 Trotti A, IJRBOP Volume 66, Issue 3, Supplement 1, 1 November 2006, Page S15

20. Arm A Arm B
Minimal tumors 60 Gy 30f 56.25 Gy in 25f <= 2/3 of vocal cord
6 weeks 5 weeks
Larger tumors 66 Gy in 33f 63 Gy in 28f
6.6 weeks 5.6 weeks
Use of 2.25-Gy f and shorter overall superior local control compared to 2-Gy
fractions without adverse reactions from the greater fraction size
2012

21. A randomized study of hyperfractionation versus conventional fractionation in
T2 Squamous cell carcinoma of the vocal cord (RTOG 95-12)
Study CLOSED following complete accrual
STRATIFY:
T2a R
T2b A Arm 1: Standard fractionation (SF)
N 70Gy / 35 f / 2 Gy daily / 7 wks
ELIGIBILITY:
D
N category: N0 O
M
Age: >18.
I
Karnofsky >= Z Arm 2: Hyperfractionation (HF)
60 E 79.2Gy / 66 f / 1.2 Gy BID / 6.5 wks
ACCRUAL:
Primary Outcome: Local control
240 patients
Secondary Outcomes: Toxicity, overall and
2012 disease free survival
The trial was designed to detect a 55% reduction in the yearly
hazard rate for local failure with 80% statistical power.

22. "A Randomized Trial of Hyperfractionation vs. Standard Fractionation
In T2 Squamous Cell Carcinoma of the Vocal Cord"
• Local control was modestly higher with HFX compared to standard
fractionation for T2 carcinoma of the vocal cord, but the difference
did not reach statistical significance
• With only 58 local failures, the statistical power of detecting the
observed 35% hazard reduction is only 36%. There was a trend for
better disease free survival with HFX.
• Results are consistent with other studies showing a modest benefit
2012
for altered fractionation in cancers of the H&N.
Trotti A, IJRBOP Volume 66, Issue 3, Supplement 1, 1 November 2006, Page S15

23. IMRT for Early Glottic Cancer
• Pros
– Potential normal tissue sparing:
– Carotid arteries
– Potential reduction in the incidence of
CVA
• Cons
– Results with IMRT uncertain
– Good results with conventional planning
– Severe complications rare
2012
– Target miss with IMRT
Albert Tiong, Waldron J, O Sullivan B et al

24. Parallel Opposed Pairs (POP)
GTV
2012
Albert Tiong, Waldron J, O Sullivan B et al

25. Radiotherapy Technique (IMRT)
Cord
PRV
PTV
CTV
2012

26. 2012

27. 2012

28. 2012

29. Technical Issues in Radiotherapy of
Advanced Laryngeal Cancer
• Target Volumes
– Larynx and entire neck are usually treated
• Primary
– GTV targeted with full dose (e.g. 70 Gy in 7 weeks)
– Elective dose to the surrounding volume (1.5 cm)
– Tracheostomy, if present, should be included in the elective dose
target
• Neck
– Gross nodes targeted with full dose (e.g. 70 Gy in 7 weeks)
– elective irradiation of Levels II, III, and IV (e.g. 50 Gy in 25 fractions)
– Additional coverage of level V, high level II into the retro-styloid
space, and retropharyngeal nodes if indicated by extent of nodal
2012
disease

30. Landmark Studies: Laryngeal Preservation
in Locally Advanced Laryngeal Cancer
• The Department of Veterans Affairs
Laryngeal Cancer Study Group (1991)
• The European Organization for Research
and Treatment of Cancer (1996)
• Radiation Therapy Oncology Group 91-11
(2003)
2012
Evaluation of place of standard radiotherapy with several strategies

31. VA Larynx Trial
• 85% of patients had at least a PR with induction PF
• 31% of patients in the induction arm had a CR at the primary site
after 2 cycles of chemotherapy and 49% had a CR after 3 cycles
• 15% of patients did not have at least a PR to 2 cycles of PF and
thus required a laryngectomy
• 64% of the patients in the chemotherapy and radiation arm were
able to preserve their larynx
• Overall survival was equivalent between the surgery arm and the
larynx preserving arm
2012
NEJM 1991

32. Intergroup 91-11
• Built on questions raised by the VA
study
• We can preserve the larynx but is
chemotherapy plus radiation better
than radiation alone?
• What about concurrent chemoradiation?
2012

33. RTOG 91-11: Larynx Preservation Trial
Phase III larynx preservation trial: induction chemotherapy and radiation therapy vs
concomitant chemotherapy and radiation therapy vs radiation therapy alone
CR, PR x 3 d cycle RT
Location R
S 1. Glottic A
2. Supraglottic Arm 1: CDDP/5-FU x 2 cycles
T N
R T Stage D
A 1. T2 O NR surgery RT
2. T3, fixed cord
T 3. T3, no cord fixation
M
I 4. T4, with base of tongue ≤ 1 cm I Arm 2: Radiation therapy + CDDP
F Z
Y N Stage E Arm 3: Radiation therapy alone
1. N0, N1
2. N2, N3
Radiotherapy: 70 Gy in 35 f in 7 weeks
Chemotherapy
2012 Arm 1: cisplatin 100 mg/m2/5-FU 1 gm/m2/24 hrs CVI x 120o q3wks x 3
Arm 2: cisplatin 100 mg/m2 Days 1, 22, 43 of RT
Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098

34. Intergroup 91-11
2012

35. RTOG 91-11: Larynx Preservation Trial
• The median follow-up among surviving patients: 3.8 years
• Demographics: median age 59 yrs; 94% KPS ≥ 80; 50% N0;
68% SGL; 28% N2-3
Arm cDDP/5-FU → RT/cDDP RT
RT
Enrolled, n (evaluable) 180 (173) 182 (172) 185 (173)
2-yr laryngectomy FS, % 59 66 53
5-yr DMFS, % 85 88 78
5-yr DFS, % 38 36 27
5-yr OS,% 55 54 56
• Conclusions
– RT/cDDP: stat signif ↑ in LFS (P = .01)
– No SS diff in survival
2012
Forastiere AA, et al. N Engl J Med. 2003;349:2091-2098

36. Intergroup 91-11
• The rate of distant metastasis was the same between
the induction group and the concurrent
chemoradiotherapy group
• Overall Survival was the same between the 3 groups
approximately 55% at 5 years
• This trial made concurrent chemo-RT the standard of
care for larynx preserving therapy.
• Notably, the comparison was to standard fractionation
radiotherapy (70 Gy in 7 weeks), known to be inferior
to altered fractionation (e.g. RTOG 9003 and MARCH
2012
meta-analysis etc)

37. Has Induction Done its Job ?
After paving the way for Organ Preservation
• MACH-NC meta-analysis:
– > 10,000 patients in 63 trials
– Significant survival benefit for concurrent
chemotherapy
– but not for neoadjuvant chemotherapy
added to radiation (minimal effect)
2012
New Strategies are emerging: TPF +/- Cetuximab
Pignon et al 2000 Lancet
Pignon et al 2009 Radiat Oncol

38. Adverse Effects of XRT in the
Treatment of Laryngeal Cancer
• Acute (during treatment)
– Mucositis
– Odynophagia
– Skin reaction
• Intermediate
– Laryngeal edema
– Xerostomia
– Taste dysfunction
• Late (should be uncommon)
– Stricture and fibrosis
– Radionecrosis
2012 – Hypothyroidism (10-20%)

39. Conclusions about the use of Radiotherapy
for Laryngeal Function Preservation
• Treatment of laryngeal cancer remains controversial,
especially in early disease
– Modality based controversies predominate
• Radiotherapy underpins function preservation strategies in
all stages of the disease
• In advanced disease, laryngeal preservation is accepted as
an appropriate goal in a functioning larynx
– How to accomplish remains controversial
– Multiple options exist, including surgery
– Concurrent chemo-RT remains the goal standard
• Research should focus on survival, function, choice of
patients for trials, translational research
2012
• We should not forget the elderly patients from the
standpoint of clinical trials