1) Altered fractionation radiotherapy, such as hyperfractionation, can improve survival rates for head and neck cancer compared to standard radiotherapy alone. Hyperfractionation was shown to improve survival by up to 8% according to the MARCH meta-analysis. 2) Intensity-modulated radiation therapy (IMRT) allows for more precise dose delivery to tumor volumes while reducing dose to surrounding healthy tissues, improving outcomes. However, it requires strict quality control protocols to minimize risks from issues like poor delineation or setup errors. 3) Studies show IMRT reduces risks of side effects like xerostomia and blindness compared to other techniques, with one study finding no cases of blindness in patients

1. The International Federation
of Head and Neck Oncologic Societies
Current Concepts in Head and Neck Surgery and Oncology 2012
Radiotherapy
for Head and Neck Cancer
Brian O Sullivan
1

2. Outline / Scope
• Radiobiology of fractionation (normal tissue and tumor
effects)
– Altered fractionation (MARCH meta-analysis)
• Precision radiotherapy
– IMRT etc
– Radiotherapy quality
– Late toxicity and strategies
• Interaction with other treatments
– Chemotherapy (sequential, concurrent)
2012
– Biotherapy (targeted agents)

3. 2012

4. Why do we Fractionate Radiotherapy?
2012

5. 2012

6. 2012

7. 2012

8. Altered Fractionation
• Accelerated Fractionation:
– Strategy: Shorter treatment time to combat tumor proliferation has an
advantage if enough dose administered; intense proliferation during
treatment commences in the 3rd week approximately (possibilities
include finishing treatment close to this time or start accelerating at this
time)
– Generally:
• More than once daily to reduce single dose exposure intensity - this
often involves reducing fraction size
• Alternatively eliminate week-end breaks, or double up several day(s)
per week, or give a concomitant ‘boost’ when proliferation starts
• Hyperfractionation:
2012 – Strategy: Use smaller dose per fraction more than once daily to
ameliorate damage to late responding tissues.

9. MARCH (Meta-analysis of Radiotherapy in
Carcinoma of the Head and Neck) Bourhis et al
7 weeks Hyperfractionated
6 weeks
5 weeks Moderately
accelerated
4 weeks
3 weeks
Very
2 weeks accelerated
50 Gy 60 Gy 70 Gy 80
Gy
2012
Altered Fractionation (BID) means different things

10. MARCH
Lancet
2006
MARCH: Meta-Analysis of Radiotherapy in Carcinomas of Head &
Neck (n= 6,515)
à Altered fractionation radiotherapy (RT) improved survival as
compared to
standard RT: Absolute benefit 3·4%
à 8% using Hyperfractionated RT with augmented dose
MACH
-­‐
NC:
Altered
the
landscape
in
head
and
neck
cancer
MACH-NC
Lancet
2000
MACH-­‐NC:
Meta-­‐Analysis
of
Chemotherapy
in
Head
&
Neck
Cancer
(10,741)
2012
à Chemotherapy
(CT)
added
to
RT,
improved
survival
by
5%
à 8%
using
concurrent
chemo-­‐RT

11. MARCH
Lancet
2006
MARCH: Meta-Analysis of Radiotherapy in Carcinomas of Head & Neck
(n= 6,515)
à Altered fractionation radiotherapy (RT) improved survival as
compared to
standard RT: Absolute benefit 3·4%
à 8% using Hyperfractionated RT with augmented dose -
Under-emphasized
MACH
-­‐
NC1
:
Altered
the
landscape
in
head
and
neck
cancer
MACH-NC
Radiother
Oncology
24
addiLonal
trials
(85%
concurrent)
2009
~
6000
addiLonal
paLents
MACH-­‐NC:
Meta-­‐Analysis
of
Chemotherapy
in
Head
&
Neck
Cancer
(17,346)
2012
à Chemotherapy
(CT)
added
to
RT,
improved
survival
by
4.5%
à 6.5%
using
concurrent
chemo-­‐RT
-­‐
Evolving
nature
of
Head
and
Neck
Cancer

12. Loco-Regional Failure
MARCH
Meta-Analysis of Radiotherapy
in Carcinomas of Head & neck
24%
Meta-
Analysis Hyperfractionation
2012
Bourhis et al. Lancet 368: 843-54, 2006

13. Loco-Regional Failure
MARCH
Meta-Analysis of Radiotherapy
in Carcinomas of Head & neck
Meta- 24%
Analysis Hyperfractionation
Cancer death
Cancer death
22%
2012
Bourhis et al. Lancet 368: 843-54,
2006

14. 8.2 +/- 2.6
% Overall Survival
Accelerated
by Treatment
Arm According
fractionation w/o total
Hyperfractionat
ion dose reduction
to the Type of
Radiotherapy
Accelerated fractionation All 3 groups
with total dose reduction combined
2012
Bourhis et al, Lancet 2006

15. MARCH
Lancet
2006
MARCH: Meta-Analysis of Radiotherapy in Carcinomas of Head & Neck
(n= 6,515)
à Altered fractionation radiotherapy (RT) improved survival as
compared to
standard RT: Absolute benefit 3·4%
à 8% using Hyperfractionated RT with augmented dose -
Under-emphasized
2012

16. IMRT for Head and Neck Cancer
• Technologically robust means of improved dose delivery:
– Exquisite sharp dose gradients especially in areas of crucial interphase (Tumor vs
Normal tissue)
– Delivers optimized non-uniform beam intensities to precisely delineated target
volumes
– Improved outcomes (especially normal tissues)
• Requires specific approach:
– Immobilization and set-up issues and knowledge of uncertainties
– Optimal imaging modality acquisition and registration
– Clearly identified dose specification and prescription regarding dose-volume
constraints
– Quality control on the whole procedure from Object delineation to delivery
– Knowledge of the pitfalls that exist (poor delineation, dose dumping, erratic
planning, tumor or normal tissue deformation and set up uncertainties emerging
throughout treatment)
2012

17. 2012

18. 2012

19. 2012

20. IMRT requires formalized Policies and Procedures
Treatment plan as a Treatment plan as an
unique event instance in a process
• Specific • General
• Neglect history • Monitor processes
• Make up rules as needed • Establish guidelines
based on information
• Anecdotal learning • Demonstrated good
practices
• Novel • Innovative and nimble
• Oral history • Shared protocols
• Skills limited to few staff • Widely used tools
2012
Courtesy of Dr S Breen, Medical Physics

21. Theodore S. Hong, Wolfgang A. Tomé, Richard J. Chappell, Paul M. Harari, Univ of
Wisconsin
H&N IMRT
Practice
Heterogeneity
Variations in Target
Delineation for Head
and Neck IMRT:
International Survey
2012
Courtesy of Dr P Harari

22. PMH H&N Site Group (8 Radiation
Oncologists with Agreed Policies)
2012
Courtesy of Dr J Waldron

23. Summary of evidence for IMRT in head
and neck cancer
• Amelioration of normal tissue effect:
– Xerostomia and QOL (3 RCTs and numerous cohort
studies)
– Blindness and ORN
• Improvement:
– Dramatic for loco-regional control (NPC)
• Comments:
– In some situations cannot perform trials due to normal
tissue sequelae (e.g. advanced NPC)
– Strong support for NPC and Paranasal (efficicacy and
morbidity)
– Other cancers: efficacy data weaker, but tissue
protection is strong
2012

24. 2012

25. Late toxicity:
Late toxicity greatest score at =/
>6 months after Day 1 of RT
In 74 patients, none developed
IMRT-related blindness (Grade 4
ocular toxicity).
2012

26. N = 176 patients, 75% and 50% had received >65 Gy and >70 Gy to >1%
of the mandibular volume, respectively
At a median follow-up of 34 months no cases of osteoradionecrosis have
taken place
2012

27. et
tolf U,
tz K, Lu ofile
P , Gra risk pr
ug uenin nimized T ).
ults: len R, H : mi apy (IMR
ible
lar res , Zwah e mand ion ther
Simi der S is of th t
radia 3 - 8.
G, Stu ro s ted
St uder radionec -modula 2(5):28
teo ity ;18
a l. Os g intens ol. 2006
n
llowi th 75% k
N = 176opatients, er On and 50% had received >65 Gy and >70 Gy to >1%
f en
S trahl
of the mandibular volume, respectively
At a median follow-up of 34 months no cases of osteoradionecrosis have
taken place
2012

28. NPC IMRT: Parotid Sparing
Randomized trials of IMRT vs 2D-RT
51 pt (T2N0-1M0) 60 pt (T1-2N0-1M0)
Pow, IJROBP 2004 Kam, JCO 2007
Significantly better recovery of salivary flow
2012

29. 2012

30. IMRT in NPC
• Many of these patients
were treated with
concurrent chemotherapy
2012
• Need new approaches to
improve systemic outcome

31. NPC IMRT: Tumor Control
Author Rate Local Nodal Distant Survival
Bucci 4-y 96% 98% 72% 74%
Wolden 3-y 91% 93% 78% 83%
Kam 3-y 92% 98% 79% 90%
Kwong1 2-y 100% 94% 94% NR
Kwong2 2-y 96% - 94% 92%
Chong 3-y 99% 99% 88% 86%
SW Lee 2-y 88% 88% 90% NR
2012

32. Potentially the biggest hurdle in accomplishing
2012
organ preservation.

33. 2012

34. Recurrence in Spared Parotid Region
Pre-treatment MRI
& Dose distribution
Recurrence PET/CT
2012
Cannon & N Lee, IJROBP 2008

35. For deficient versus compliant radiotherapy Large variation in the percent of plans with major
respectively: adverse impact was noted according to country.
Even more striking:
• The 2 year overall survival:50% versus
70% (hazard ratio 1.99; P < .001) • Correlation between the number of patients
Ø 20% difference entered and the probability of receiving
unsatisfactory radiotherapy.
• The 2 year freedom from locoregional • Centers enrolling < 5 patients, 29.8% had a
failure was 54% versus 78% (hazard major adverse impact
ratio 2.37; P < .001)
• Centers enrolling > 20 patients had 5.4%
Ø 24% difference
2012

36. 24% 20%
2012

37. • Cetuximab + radiation versus radiation
alone
– Efficacious
• Locoregional disease: HR=0.68 (p=0.005)
• PFS: HR=0.70 (p=0.006) OS: HR=0.74 (p=0.03)
• Subset analysis: Best results for altered fractionation radiation
regimen (OS: HR=0.64) and in oropharynx
2012
• No increase in in field toxicity
Bonner 2006 NEJM

38. Unusual Skin Toxicity – Even in Low Dose Radiotherapy Regions
n=13
Cetux abgebrochen bei
n=9
2012
Pryor et al., Radiother. Oncol. 90, 2009,

39. ECOG 1308 - The First HPV-Unique Trial
2012
Courtesy of M. Gillison

40. 40
Forest Plot of the Hazard Ratios (95% Confidence Intervals)
by Pre-Treatment Characteristics – Five-year Update
Improvement with Cetuximab
2012
Bonner et al 2010

41. Elderly patients with malignant
disease will progressively constitute
the majority of patients in
oncological practice
Catherine Terret,
Centre Leon Berard, Lyon
2012
Terret. Expert Rev Anticancer Ther 4(3) 469-475
(2004)

42. • Physiological changes associated with ageing
• Declining renal function and decreasing reserve
in multiple organ systems predispose to
unpredictable toxicities
• Rapidly increasing population
• Laden with problems of multiple
organ systems, comorbidities (esp.
2012
vascular pathologies)
• Polypharmacy complicates situation

43. Disease Response
Pignon T et al Eur Journal
of Cancer, Vol 32A, 12,
2075-81, 1996
• 1589 patient with head and neck cancer enrolled in 5 EORTC trials (Feb
1980 – March 1995)
• 20% were >65 years
• No difference survival, loco-regional control, Acute Toxicity, Weight
loss, or Late Toxicity
• Older patients had more severe subjective symptoms (Functional acute
2012
toxicity, Grade 3 and 4, P<0.0001)
• Conclusion: chronological age is irrelevant – at least 11 years ago.

44. Elderly defined as >/= 75 years
• 2312 patients: 425 elderly (20%); 1860 Cause-specific survival in
patients who received definitive
younger (80%)
radiotherapy (n=1487) (p<0.01)
• F vs. M: 36% vs. 27%, p<0.01
• Other cancer: 23% (elderly) vs. 13%,
p<0.01
• Curative treatment; 79% (elderly) vs.
93%, p<0.01
• 760 received intensified treatment
(concurrent chemoradiotherapy or
hyperfractionated accelerated RT) (elderly
= 46) and (younger n = 714)
• No difference in tolerance to treatment
2012

45. rospective
ed for pCause-specific survival in
Elderly defined as >/= 75 years
e
ei s an urgent n adapted (n=1487)definitive
• 2312 patients: 425 elderly (20%); 1860
nd patients who received nd
Theryounger (80%)
fs tandard a head a (p<0.01)
radiotherapy
o th
aluation tients wi
• F vs. M: 36% vs. 27%, p<0.01
ev a
elderly p
• Other cancer: 23% (elderly) vs. 13%,
sch edules in
p<0.01
cancer.
• Curative treatment; 79% (elderly) vs.
neck
93%, p<0.01
• 760 received intensified treatment
(concurrent chemoradiotherapy or
hyperfractionated accelerated RT) (elderly
= 46) and (younger n = 714)
• No difference in tolerance to treatment
2012

46. Summary
• We have many radiotherapy options (technical, biological,
scheduling, prescriptive, combinations with other agents and
other treatments)
• We must refine approaches, combine modalities more
conservatively with potential equal or greater efficacy
• Molecular biology of tumors and of radiation interaction with
tissues and in combination with systemic agents and
surgery is essential
• We need especially to focus on management approaches
that meet the needs of our aging population
• Quality assurance must become an accepted part of the
delivery of high quality radiotherapy
• Clinical trials that address all domains of the practice of
radiation medicine remain the cornerstone of progress
2012