Head and Neck Conformal Therapy and IMRT Course

THE ROYAL COLLEGE OF RADIOLOGISTS
THE INSTITUTE OF PHYSICS AND ENGINEERING IN

MEDICINE
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP
Head and Neck Conformal therapy and IMRT Course

Oncology Institute Cluj-Napoca, Romania
16-18th June 2010
The Imaging Centre at St Thomas'

Programme for the three-day teaching course
Day 1 Wednesday 16th June
Session 1 Introduction
9:00 Introduction and opening remarks
V Cernea / C Nutting
9:15 Lecture 1: The 21st Birthday Party for Intensity-Modulated

Radiation Therapy (IMRT); 21 years from 1988-
2009; from concept to practical reality
S Webb
10:00 Lecture 2: Clinical application of conformal therapy and IMRT

(all tumour types)
C Nutting
10:45 Lecture 3: Practical considerations for conformal therapy and

IMRT
H McNair
11:15 -11:45 Break
Session 2 Imaging and planning

11:45 Lecture 4: Cross sectional imaging in the evaluation and
staging of head and neck cancer
J Olliff
12:30 Lecture 5: IMRT treatment planning basics

C Clark
1:00-2:00 Lunch Break
Session 3 Practical session (1)

2:00-4:00 All
Clinical Target Volume Definition CN/KJH

Physics QA SW/CC
Radiographer issues HMcN
Radiology special topics:
The parapharyngeal space JO
PET/CT in lung & oesophageal cancer SR
4:00-5:00 Topic Lectures
4:00 Lecture 6: Interfaces between classical and molecular

radiobiology
K Harrington
Dinner
1
Day 2 Thursday 17th June
Session 1
9:00 Lecture 7: Target volume definition for head and neck cancer
C Nutting
9:45 Lecture 8: FDG-PET in head and neck cancer

S Rankin
11.00-11.30 Break
Session 2
11:30 Lecture 9: Inverse planning for intensity modulated radiation
therapy
S Webb
12:00 Lecture 10: IMRT planning: strategies for improving poor plans,
common errors and plan assessment
C Clark
12:30 Lecture 11: Verification of Treatment Delivery: Role of imaging

H McNair
1:00-2:00 Lunch break
Session 3 Practical session (2)
2:00-4:00 All
Clinical Clinical plan assessment CN/KJH

Physics Planning SW/CC
Radiographer issues HMcN
Radiology special topics

Imaging the thyroid J Oliffe
PET in Oncology: FDG and Beyond S Rankin
4:00-5:00 Topic Lectures
4:00 Lecture 12: Combatting cancer in the third millennium: the

contribution of medical physics and specially
radiotherapy physics
S Webb
Dinner
2
Day 3 Friday 18th June
Session 1
9:30 Lecture 13: Quality Assurance and verification for IMRT

C Clark
10:15 Lecture 14: Combining technical radiotherapy with

chemotherapy and/or targeted drugs
K Harrington
11:00-11:30 Break
Session 2
11:30 Lecture 15: Head and Neck IMRT evidence base: Indications
and clinical outcomes
C Nutting
12:15 Lecture 16: Common pitfalls in head and neck cancer imaging
J Olliff
1:00 Closing remarks

V Cernea/C Nutting
Lunch
3
THE COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP TEAM
2 Radiation Oncologists: Dr Nutting, and Dr Harrington, Royal Marsden Hospital and

The Institute for Cancer Research, London
2 Radiation Physicists: Prof Steve Webb, Royal Marsden Hospital and The Institute for
Cancer Research, Sutton, Dr Catharine Clarke, Royal Surrey County Hospital and
National Physics Laboratory London UK
1 Treatment Radiographer: Miss Helen McNair
2 Oncology Diagnostic Radiologists:Dr Julie Olliff, Birmingham UK and Dr Sheila

Rankin St Thomas’ Hospital London UK
4
Personal profile of the lecturers
Biographical Information – Dr Catharine Clark
Catharine Clark completed her PhD in Radiation Physics in 1998 at University College
London. She then moved to Paris, France where she worked at the Institut Gustave
Roussy and then at Stanford University, California, USA. Catharine returned to the UK
in 2001 and took up a post at the Royal Marsden. She led the IMRT QA for the first
national head and neck IMRT trial and set up the UK IMRT credentialing programme.
Catharine has worked in the field of IMRT for the last 10 years and has published
widely in this area. She has lectured on IMRT on many national and international
courses. Catharine currently holds a joint post as a consultant radiotherapy physicist at
the Royal Surrey Hospital and the National Physical Laboratory, London.
5
Biographical information -Dr Kevin Harrington
Kevin Harrington is Reader in Biological Cancer Therapies and Honorary Consultant in

Clinical Oncology at the Royal Marsden Hospital. Having graduated from St
Bartholomew’s Hospital Medical School, he trained in general medicine and then
clinical oncology at The Royal Postgraduate Medical School, Hammersmith Hospital
and The Royal Marsden Hospital. He was awarded Membership of the Royal College
of Physicians and Fellowship of the Royal College of Radiologists (receiving the
Rohan Williams Medal). He completed his PhD in liposomal targeting of
radiosensitisers at Hammersmith Hospital and undertook post-doctoral research in gene
and viral therapies at the Mayo Clinic, USA. He returned to the UK in 2001 to combine
a clinical practice in head and neck cancer and melanoma with his role as Team Leader
in the Targeted Therapy Team, The Institute of Cancer Research, London. His research
interests include combining standard anti-cancer therapies with novel biologically
targeted agents. He has published over 230 peer-reviewed papers and 40 book chapters.
6
Biographical Information – Ms Helen McNair
Helen McNair trained as a Radiographer in Belfast, qualifying in 1986, after which she
worked for 2 years in Australia. On return to the UK she worked at the Westminster
Hospital then moved to the Royal Marsden NHS Foundation Trust where she worked in
a variety of roles including simulator superintendent before taking up a post as
Research Superintendent in 2000.
Helen’s area of expertise is reducing motion and imaging for verification for which she
is recognised nationally and internationally with both publications and invited talks.
She was a task group member of the ESTRO European Institute Radiography (EIR)
which recently published guidance for the evaluation of in-room IGRT systems and
was a member of the Royal College of Radiologists Working party to develop national
guidelines for portal imaging verification (On target- improving geometric treatment
accuracy).
Helen was pleased to return by invitation to Australia in 2006 as a keynote speaker at

the Australian Institute of Radiography conference and to complete a tour of 20
departments presenting to the radiographers some of the experiences of implementing
IMRT and IGRT in the UK. She also taught recently at the 2D-3D ESTRO teaching
course in Cairo.
She is a member of the British Institute of Radiology Oncology committee and is

currently writing up a PhD.
7
Biographical Information – Dr Chris Nutting
Dr Christopher M Nutting BSc FRCP FRCR MD ECMO
Consultant and Reader in Clinical Oncology, Head of Head and Neck Unit, Royal
Marsden Hospital and Institute of Cancer Research, Fulham Road, London SW3 6JJ
Dr Nutting is Consultant and Reader in Clinical Oncology at the Royal Marsden

Hospital. He specializes in the management of head and neck, thoracic and thyroid
malignancy and has a specialist interest in the application of high-technology
radiotherapy techniques and chemoradiation for a number of tumour types. He is an
International expert in Intensity Modulated Radiotherapy (IMRT), and other conformal
radiation techniques. He also has an interest in chemoradiation techniques applied to
head and neck and lung cancer.
He trained in Oncology at the Royal Marsden Hospital and St Bartholomews Hospital,

and was awarded his Medical Doctorate from The Institute of Cancer Research
(University of London). He gained specialist clinical training in New York, University
of Michigan, and a number of European Centres. He is a regular contributor to National
and International clinical meetings and has published over 150 articles in his field of
expertise.
8
Biographical Information – Dr Julie Oliffe
I have been a consultant radiologist in the UK for over twenty years. I trained on the St
George’s Hospital rotation in London and became a Senior Lecturer in Radiology at the
Royal Marsden Hospital in 1988. At that time my special interest was in CT and MRI
in oncology. In 1990 I moved to Birmingham where I have been a consultant
radiologist with an interest in CT, MR and US. Here I continued my specialist interest
in oncology but have further developed interests in head and neck imaging.
I am a founder member of the British Society of Head and Neck Imaging and member
of the European Society of Head and Neck Radiology. I lecture on national and
International courses.
I was President of the British Institute of Radiology from 2006-2008. This is a
multidisciplinary society and is the oldest radiological society in the world. It takes an
active part in both education and the setting of standards.
I have a busy service commitment in my present job but continue to perform research
and have recently been a named applicant on a successful NIHR grant to research
lymphocyte tracking in patients with liver disease. I am presently applying for an HTA
grant to investigate the role of imaging in incidental thyroid nodules.
I have served on various editorial boards and have been responsible in the past for the
organisation of the UK’s largest radiological conference.
9
Biographical Information – Sheila Rankin
Dr Sheila Rankin FRCR
Dr Rankin is a consultant radiologist at Guy’s & St Thomas Foundation trust. Her

subspecialty interest is body CT with particular reference to oncology and including
PET-CT. Dr Rankin is a past examiner for FRCR (Royal College of Radiology) and is
an external examiner for FFR (Ireland). She is past president of the International
Cancer Imaging Society. She has published papers on PET-CT in lung cancer,
oesophageal cancer and head and neck cancer. She edited a volume on oesophageal
cancer in the contemporary issues in cancer imaging series. She regularly lectures at
Royal College and International Cancer Imaging Society meetings.
10
Biographical Information - Steve Webb
Steve Webb has been Professor of Radiological Physics since 1996 and Head of the
Joint Department of Physics of the ICR/RMH since 1998. He is also a Team Leader in
Radiotherapy Physics. He has PhD and DSc degree, and is a Fellow of the Institute of
Physics (FInstP), the Institute of Physics and Engineering in Medicine (FIPEM) and the
Royal Society (of) Arts (FRSA). He is a Chartered Physicist (CPhys) and a Chartered
Clinical Scientist (CSci).
Steve has published some 200 peer-review papers in medical imaging and the physics
of radiation therapy, as well as 5 single-author textbooks and an ‘edited by’ in these
areas. He is Editor in Chief of the international journal Physics in Medicine and
Biology. He was awarded the British Institute of Radiology Silvanus Thompson Medal
in 2004 and the Barclay Medal in 2006. He has been Visiting Professor at DKFZ
Heidelberg, The University of Michigan at Ann Arbor, Memorial Sloan Kettering
Cancer Centre New York and Harvard (Mass General Hospital, Boston). He has been
an Academic Board Member of the Board of Trustees four times from 1984-1987 and
from 1996-1999 and from 2005-2011.
To give balance over the years, Steve has built and played plucked-string renaissance
instruments (and helped teach these skills), studied Italian and Spanish, and had a
lifetime interest in the Great Western Railway and in collecting and running gauge-o
clockwork and live steam trains (with an extensive library and quite a few publications
[not on the CV!]).
11
Copyright information ©
This Course Book contains the slide presentations used to support the Course. The
material is offered in good faith. Any use of the material in connection with the
treatment of patients is entirely at the user’s risk. The Lecturers assume no
responsibility although they have done their best to ensure accuracy.
The material is for the private and personal study by the individual students. It must not
be passed to any third party, re-used as part of any lecture presentation or copied
without the permission of the lecturing team 1 . A CD of the lectures is also included in
*.pdf format. There will be many movies shown during the Course which are not on the
CD.
1
Contact details:
chris.nutting@rmh.nhs.uk
12
References for books for Romania School
Reviews of the history of CFRT and IMRT, together with details of inverse-planning
algorithms can be found in four IOPP books from one of the Lecturers. These form a
sequential set and are all different. They contain long reference lists to original papers.
The AAPM 2003 IMRT Schoolbook is tutorial. Another good thing to have is the
Schlegel and Mahr DVD. (this has a very large number of pictures and movies as well
as tutorial text). Other books are recommended here. Some of the other articles are
more “chatty”.
[1] M. Alber et al.., Guidelines for the Verification of IMRT ESTRO, Brussels, Belgium, 2008.
[2] Bortfeld T, Schmidt-Ullrich R, De Neve W and Wazer D E (2006) Image-guided IMRT. Heidelberg-
Springer ISBN 10-3-540-20511-X
[3] G. A. Ezzell et al., “AAPM REPORT: Guidance document on delivery,treatment planning, and
clinical implementation of IMRT: Report of the IMRT subcommittee of the AAPM radiation therapy
committee, Med.Phys.30, 2089–2115 2003.
[4] Galvin J, Ezzell G, Eisbrauch A et al. (2004) Implementing IMRT in clinical practice: a Joint
document of the American Association of Physicists in Medicine. Int. J. Rad. Oncol. Biol. Phys. 58, No.
5, pp. 1616–1634
[5] James H, Beavis A, Budgell GJ, Clark CH, Convery DJ, Mott JH. Guidance for the clinical
implementation of intensity modulated radiation therapy. Institute of Physics and Engineering in
Medicine. Report no 96; 2008
[6] Mundt A J and Roeske J C (2005) Intensity-modulated radiation therapy – a clinical perspective.
Hamilton: BC Decker Inc ISBN 1-55009-246-4
[7] Palta J R and Mackie T R (2003) Intensity modulated radiation therapy: the state of the art AAPM
Monograph 29 (AAPM Summer School 2003 Colorado Springs)
[8] Korreman S, Rasch C, McNair H, Verellen D, Oelfke U, Maingin P, Mijnheer B, KhooV. The
European Society of Therapeutic Radiology and Oncology-European Institute of Radiotherapy (ESTRO-
EIR) report on 3D CT-based in-room image guidance systems: A practical and technical review and
guide. Radiother. Oncol. 2010, 94(2):129-44
[9] R Timmerman and L Xing (2009) Image-guided and adaptive radiation therapy Wolters Kluwer /
Lippincott Williams and Wilkins ISBN 978-0-7817-8282-1
[10] Webb S. (1993). The physics of three dimensional radiation therapy : conformal radiotherapy,
radiosurgery and treatment planning. Bristol: IOP Publishing. ISBN 0-7503-0254-2 Pbk 0 7503-0247-
X Hbk
[11] Webb S. (1997). The physics of conformal radiotherapy: advances in technology. Bristol: IOP
Publishing. ISBN 0 7503-0397-2 Pbk 0 7503-0396-4 Hbk
[12] Webb S. (1998). “The physics of radiation treatment.” Physics World November 1998, 39-43.
[13] Webb S. (2000). Intensity modulated radiation therapy. Bristol: IOP Publishing. ISBN 0 7503 0699
8 Pbk (no Hbk)
[14] Webb S. (2002). “Some snapshots from the history of radiotherapy physics.” SCOPE 11: (1) 8-12.
[15] Webb S. (2004) Contemporary IMRT-: developing physics and clinical implementation Bristol: IOP
Publishing. ISBN 0 7503 1004 9 Hbk (no Pbk)
[16] On target document can be found at
http://www.rcr.ac.uk/docs/oncology/pdf/BFCO(08)5_On_target.pdf
13
Wolfgang Schlegel’s e-book is:
3D Conformal Radiation Therapy

A multimedia introduction to methods and techniques
2nd revised and enhanced edition
Springer Verlag Berlin Heidelberg
is a member of Springer Science + Business Media
ISBN 3-540-14884-1 Editors:
Wolfgang Schlegel and Andreas Mahr
Deutsches Krebsforschungszentrum
(German Cancer Research Center)
Im Neuenheimer Feld 280
Steve’s books look like:
14
LECTURES:
SLIDE
HANDOUTS
Day 1 Session 1 Lecture 1
9:15am
Joint
I come
means……….
from the Institute of
Cancer Research and the Royal
Marsden Hospital, London, UK
Steve Webb
Institute of Cancer
Research
(University of
London)
and Royal Marsden
Hospital, UK
One cannot really

The 21st Birthday Party for Intensity-Modulated
imagine one without
Radiation Therapy (IMRT); 21 years from 1988-2009;
from concept to practical reality the other. There is
Romania June 2010 great strength in this
unity
The “Royal” in the Royal Marsden Hospital, London, UK
Sheffield doctor:
William Marsden
Even I can’t remember this far back
1st medical physicist at RMH Major

Charles Phillips (gentleman scientist)
Joint Department of Physics The development of Intensity-modulated

radiation therapy (IMRT)
• About 150 physicists, roughly 50% NHS (RMH)
employees, 50% university (ICR) IMRT has made a major clinical impact
• Mix of research, clinical service, teaching and improving the precision of delivery of high dose
business – no hard boundaries
• Excellent interaction with key clinicians
to tumours while sparing organs at risk.
• Teams: radiotherapy physics, nuclear medicine
physics (imaging and therapy), ultrasound and MR How has the field reached the present position?
physics, x-radiology and protection services
• About 25 PhD students at any one time
• Heavily grant supported from CR-UK, EPSRC,
industry,….EU
Wednesday 16th June 2010 1

9:15am
Professor Anders Brahme

How IMRT works 1988 famous paper on inverse planning
Series of lecture tours “assisted” IMRT elsewhere in key centres
You see the 9 modulated beams and the corresponding conformal dose 1982 Brahme et al discussed inverse-planning for a
map built up.
(DKFZ, MSKCC, ICR-RMH…….)
fairly special case of rotational symmetry.
1895 The x ray was discovered on November 8th in Germany by

Prehistory Röntgen.
1896 Doctors understood the need to “concentrate radiation” at the
target but had means to neither do this nor even to know where the
target was precisely.
Hindsight is wonderful.
What came before 1988?
The London Hospital (I think) in 1906
Synchronous aperture “Concave

shaping and shielding isodoses”
by Proimos. in 1961!
1970s The Royal Free Hospital built the “tracking
cobalt unit” and MGH Boston did similar tracking
This is (nearly) the principle of IMRT with a linac.

9:15am
Overview of 114 years of radiotherapy
Minimise unwanted dose to

normal tissues
Tumour
Note increased sparing of normal tissue
1950s Takahashi first discussed Traditional cross-fire therapy Rotation therapy Conformal therapy
conformation therapy. including Intensity
The Gscheidlen MLC patent of 1959 Modulated Radiation
& Therapy (IMRT)
The Brahme/ Scanditronics MLC of 1984

(ESTRO3) 1896-
1896-1950 1950s 1990
1990--2010s
Why do we perform Intensity

Modulated Radiation Therapy
(IMRT)?
An example of why we want a concave dose distribution

Prostate and Pelvic Node Clinical IMRT Trial. A typical
transaxial section looks like this.
bladder
rectum
prostate

9:15am
An 2nd example of why we want a concave Frame sequence

dose distribution 1) Pink: body
contour PTV1
95%
2) Dark green: 90%
thyroid
PTV2
3) Light green: 95%
nodes 90%
4) Switch off
body contour
Head & Neck
5) Yellow cord [movie progresses
6) Grey: from superior to
oesophagus inferior]
Message: Note the sparing

complex
planning case! of the cord
(orange) by
Courtesy of
highly concave
Mike Partridge
Head & Neck isodoses
PTV1
95%
90%
PTV2
95%
90%
Note sparing
of the cord (1st
yellow) and
one parotid
(2nd yellow)
Head and neck IMRT patient
(transaxial (left); coronal (right))
Parotid sparing of a tonsil IMRT patient who is being
treated to 65 Gy to the primary PTV and 54 Gy to the nodes in 30 fractions.
The spared parotid can be seen at the top right of the image on the right.
phase 3 trial randomised between conventional RT and IMRT.
Early milestones in inverse

planning
The key historical stages leading to inverse planning were:
(i) <1920s: no planning,

(ii) 1920s-1960s “hand planning” (overlay of isodose curves on
transparencies),
(iii) 1960s computer planning (firstly in 2D, then in 3D). This was “forward
planning”,
(iv) 1982 first analytic inverse-planned problem,
(v) 1988 Censor and Brahme independently published first papers on
algebraic inverse planning.
(vi) 1988 Källman postulated dynamic therapy with moving jaws.
(vii) 1989 Webb developed simulated annealing for inverse planning. So did
Mageras and Mohan.
(viii 1990 Bortfeld developed algebraic/iterative inverse-planning, the
precursor of the KONRAD treatment-planning system.
(ix)1991 Principle of segmented-field therapy developed (Boyer / Webb).
(x) 1992 Convery showed the dMLC technique was possible.
(xi) 1992 first commercial inverse-planning system,

9:15am
Dramatic news in Geneva. October 20th 1992
11 th 1st truly IMRT delivery equipment

– the World’s
Session: winter 2008
Symbolising the
essence of IMRT
Mark Carol at 12th ICCR Conference 1997 [on roller blades]
1992 Carol first showed the NOMOS MIMiC and associated PEACOCKPLAN planning system CORVUS).
1992 Mark Carol: MEDCO and NOMOS

The NOMOS
MIMiC • Geneva WHO meeting.
• The MIMiC.
• Peacockplan.
• CORVUS.
• Not announced until 100% (well 99%) ready.

Hook up and start; 4 years lead on dMLC; integrated planning and
delivery.
• Durango and the Strater Hotel
NOMOS IMRT dominated (USA)
Clinical delivery 1994-1997
Compulsory hat wearing at World’s 1st IMRT School in 1996
In 1993 Thomas
Bortfeld and Art How IMRT works
Boyer made the first
IMRT s-&-s delivery You see the 9 modulated beams and the corresponding conformal dose
in Houston using a map built up.
Varian machine and
taking about 3 hours
to reset fields by
hand. They drew this
graphic 3D display of
dose.
History (above) is now repeated as a

QA experiment (left)

9:15am
How to make a 2D complex modulation by leaf Dynamic multileaf collimator (dMLC) IMRT delivery
sweep and step-and-shoot with a MLC
• Technique
Leaves move only one way; radiation off
between moves • 3 groups in 1994 (Stein et al / Spirou and Chui /
Svensson et al – all had the same maths.
3D Conformal Radiation Therapy
A multimedia introduction to
• From “one-off” to market leader (?) – commercial
methods and techniques
2nd revised and enhanced edition
thrust via Varian, Elekta, Siemens…
Springer Verlag Berlin Heidelberg
is a member of Springer Science +
Business Media
ISBN 3-540-14884-1
Editors:
Wolfgang Schlegel and Andreas
Mahr
Deutsches
Krebsforschungszentrum
(German Cancer Research
Center)
Im Neuenheimer Feld 280
Some IMRT early inventors:

Jorg Stein, Thomas Bortfeld, Dick Fraass, Wolfgang Schlegel and
Steve Webb (ESTRO Edinburgh 1998)
Institute of Cancer Research (ICR)/ Royal Marsden Hospital (RMH) were part
of the Elekta International IMRT Consortium since it was founded by just 8
people in 1994. This was wound up once clinical IMRT was no longer regarded
as a “research-only” activity
1993 Tomotherapy (the Wisconsin machine) first described by Mackie. (August 2002 the first
clinical treatments)
My view is not the only one
•Everything
•Disclaimers! important has
•Reviewers of history tread happened in the last
dangerously. 21years.
•True versus amateur •So vast majority of
historians. pioneers are (i) alive
•Agreement of major (ii) still working
landmarks vs controversy on •If I mention key
the detail – A.N. Other may tell names do I make
the story differently. instant enemies? I
hope not

9:15am
Prostate tomotherapy delivery
(Swerdloff) Collimator as in NOMOS MIMiC and in Wisconsin Tomotherapy machine
Clinical implementation of IMRT by

the Multi-Leaf Collimator (MLC)
method in London, UK
• ICR/RMH 1st patient Sept 20th 2000 at Sutton
The motion of internal markers is detected
by x-rays; motion of external markers is
(prostate + pelvic malignancy). Patients now about
detected by infrared. Motions are 300+.
correlated every 10s. Monitor of external
markers by i.r. then translates to
• First prostate and node patient at Chelsea July 2001.
movement of internal tumour markers in • First H&N IMRT was treated in Chelsea in April 2002.
almost real-time and this is fed back to the
robot. • First H&N treated in Sutton in August 2003.
• Memorial Sloan Kettering Cancer Centre 1995->.
• Evidence for efficacy.
Cyberknife
Number of patients treated with IMRT at RMH London

(July 2001-March 2010)
Inverse Planned IMRT Treatments
70 140
The Royal Marsden (Sutton) Sarcoma/other
120 Head & Neck

60 PPN total 151 PPN H&N
Prostate & Nodes
100
H&N 76 LUNG PAED
50 56
Number
80
Paed 9
60
60
40 Lung (VMAT) 4
Patient numbers 40 47
27
30 21 15 56 14
20 11 37
8 17 17 22 17 20
8 15
0 0
3
20
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year
10
0 •Total number treated: 488

2000 2001 2002 2003 2004 2005 2006 2007 2008
•212 PPN
Planning Systems used: 2000 Corvus; 2001 – 2003, Helax;
•259 H&N
2004 – 2008, Philips Pinnacle (DMPO), except Lung: AutoBeam + Pinnacle.
•17 Sarcoma
CT based treatment planning increased from 400 to 2100 patients per year
over this period. Forward planned, segmental IMRT for breast, prostate and •Significant increase in 2008 due to change in QA from
rectum tumour sites in 2008: 150 patients per year. measurement to calculation based MU verification
Courtesy of Jim Warrington From Margaret Bidmead

9:15am
Inverse planning and IMRT at DKFZ-Heidelberg

(slide courtesy of Wolfgang Schlegel) Inverse Planned IMRT Treatments
IMRT patients at dkfz
dkfz, Heidelberg
250
250
200
200
150
patients
150
100
100
50 50
0
0
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
ye ar
Patient number Prostate 154 Lung Cancer/Pleuramesothelioma 98
Head and Neck 280 Chordoma/Chondrosarcoma 148
Meningeoma 98 Pancreas 91
Start of IMRT treatment at dkfz: 1997 Mamma-Ca 25
others 334
Oesophagus-Ca 43
IMRT and IGRT What is Image Guided Radiation

Therapy (IGRT)?
New technology =
All radiotherapy techniques that rely on the use of (generally 3D or
4D) images
[1] New technology for image guided To solve what problems?
radiation therapy; At planning stage: (1) Disease staging and determining the GTV
and CTV, (2) Assessing change of target, need to re-plan,
adaptive therapy
[2] New technology for IMRT delivery Pre- (each) treatment fraction: Positioning patient correctly
(interfraction motion correction)
(these two are today intrinsically linked) During each fraction: Intrafraction motion correction by either (1)
gating, (2) breath-hold (3) tracking
Post-therapy: Assessment of response
What technology can assist? New Technologies to deliver IMRT

…and is it available in the UK?
[In UK: Widely clinically available; clinically available First 3 allow inter-fraction position adjustment
in some Centres; mainly “under development”]
[1]* “Viewray”: MRI and Co60 IMRT combined in one integrated unit (3 Co sources;
• Target volume definition • PET, SPECT, MRI,, CT Dempsey group Florida)
[2] † MRI and linac combination (Utrecht; Lagendijk)

• Treatment planning • kV x-ray film
[3]#Tomotherapy; slice-based/helical (Nomos/Tomotherapy
• MV film, EPID, MVCT Corporation)
• Beam delivery verification
Next 3 allow intrafraction motion correction
• Optical markers, Ultrasound, MVCT, kVCT,
• Interfraction motion Implanted markers (x ray opaque or magnetic) [4]* Dynamic “breathing leaves” MLC
• Optical markers, kV stereo-imaging, [5]#Robotic IMRT with Synchrony imaging (Sunnyvale: Accuray)
Ultrasound, Implanted markers (x-ray opaque
• Intrafraction motion [6]#Dynamic-shaping of fields via double-bank MLC and EPID on circular rails
or magnetic)
(TrackBeam)
_____________________________________________
• Breathing control (audio-visual; held-breath;
* Concept only † In progress since 2000 # Available now
• Intrafraction correction spirometry), Linac gating, Tracking MLC

9:15am
Fluoroscopy to show moving lung / lung tumour

VMAT
Can vary:
[1] gantry speed; Same patient
[2] fluence output rate;

[3] MLC field shapes;
[4] MLC orientation
all dynamically
No-one really knows a general
theory. Sometimes (but not Note the variability
always; often the reverse) can of motion
get better conformality with Different patient
fewer MU. Courtesy of James Bedford and Motion and its
(courtesy of
Jim Warrington variability are the
Helen McNair)
enemy!
Synchronised Delivery
MLC
motion
MLC
motion
For the future………..

Dr Dualta McQuaid has shown that synchronised leaf tracking can be
performed on an Elekta linac – first in the world to do this and just
published
Questions and Challenges

technology
normal unregulated breathing
intensive • How quantitative is functional imaging?
regular breathing • When is IGRT needed?
real time tracking – High dose treatments without IGRT?
voluntary breath hold • How do methods compare?
predictive tracking imposed breath hold – Same/extra information, dose, time, cost?
• How good are surrogates?
sedation
gating with free breathing – Internal markers, external markers
or breath hold anaesthaesia • How reproducible is intra-fraction motion?
– Can we measure it sufficiently accurately before irradiation?
standard fixed delivery patient – Can it be controlled?
intensive – Can predict-ahead methods be made to reliably work?
• How does it change our treatment margins and doses and what
are consequences for patient?
Slide courtesy of Prof Solutions to tumour
Mike Brada
motion in NSCLC RT From Dr Phil Evans

9:15am
And the press has been Conclusions on IMRT delivery

interested following
David Dearnaley’s • In 1988 when inverse planning seriously began there was no
initiative…. IMRT delivery equipment except compensator;
• In 1992 MIMiC slice tomotherapy became available;
• In 1994 the MLC MSF and the dMLC method had been
operated by a few centres in a research setting;
• By 2000 commercial MLC/Linac manufacturers have made
available MSF-MLC and dMLC technique linked to inverse
planning;
• By 2010 Many centres in Europe, USA and Asia regard IMRT as
a clinical necessity;
• Clinical implementation still requires multiskills of doctors,
physicists, radiographers, engineers all working together. It is
not quite “turn key”;
• Watch out for robotics (especially for motion correction), for
simpler IMRT (to meet a call from less well off places) and
(possibly) an anti-IMRT backlash from diehards.
• Motion is the enemy! Maybe the IMRT problem is solved and
the IGRT problem is now the real one to address.
Detailed descriptions of
both theoretical and
practical IMRT + huge
lists of primary
references can be found
in these 4 sequential
books
1993 1997
2000
2004

10:00am
Clinical application of conformal Introduction

therapy and IMRT
• Radiation therapy is a key treatment modality
in Head and Neck Cancer
Dr Christopher M Nutting MD FRCP FRCR
• Primary therapy
Consultant and Reader in Clinical Oncology,
• Offers cure rates similar to surgery for early disease
Head and Neck Unit, Royal Marsden Hospital & Institute
• Allows organ preservation and retains function
of Cancer Research, Fulham Road, London
• Post-operative therapy
• Maximises cure rates and permits conservative surgery
Aims of Radiotherapy in Head Pre-radiotherapy assessments I

and Neck Cancer • Accurate diagnosis
– Specialist pathology review of biopsy/FNA
1. To achieve tumour control by delivering a • High concordance for SCC (90%)
homogeneous tumouricidal radiation dose • Essential for salivary/lymphoma/early invasion
to tumour-bearing tissues – Full analysis of post-operative resections
2. To avoid radiation-induced complications • Does the resection confirm the pre-op diagnosis
by minimising dose to normal tissue – Assessment of primary site by EUA/imaging
structures • Typically complementary to each other
Pre-radiotherapy assessments II
• Accurate staging
– Assessment of tumour extent
• EUA and biopsy
– Pathological staging in post-op cases
• Margins, ECS, LVSI, PNI, lymphatic levels
– Imaging of primary site, neck and chest
• CT, MRI, PET/CT

10:00am
Pre-radiotherapy assessments III

• Patient factors
– General fitness (performance status)
– Medical History: CVS, RS, kidneys
– Able to lie in treatment position
– Previous radiotherapy
– Organ function
– Airway and nutrition
– Patient choice
– Biomarker: EGFR status, HPV status
Understanding of natural history of Local spread of NPC

each sub-site and pathology
• Primary tumour • 2 routes
– Local spread- mucosal, deep soft tissue, paths of least – Parapharyngeal space
resistance, special cases (e.g. ACC)
(IX-XII + sympathetic
• Nodal spread chain)
– Groups at risk, levels, incidence in N0 and N+
– Supero-lateral via F.
– Lateral vs midline CTV: Unilat or bilat irradiation
Lacerum to Cav Sinus
– 10-20% risk cut-off usually used for elective irradiation (II-IV)
– Lindberg 1972…..
Radiation doses for wide-field

Concepts of ICRU applied to HNC
irradiation
• GTV: demonstrable macroscopic disease from Dose conv frac
physical findings and imaging
Primary site and involved nodes 66-70Gy 33-35#
– Tumour and enlarged nodes
• CTV: Potential sites of microscopic cancer spread Elective nodal groups un-operated 50Gy 25#
– Around the primary and involved nodes
– Elective neck nodes Post-operative high risk sites 60-66Gy 30-33#
• PTV: CTV with a margin for movement and set-
up uncertainty

10:00am
Accelerated hypo-fractionated UK Diagnosis, Staging , Patient factors OK

Radical RT
radiation doses for small volumes thought
pathways for Tumour CTV
Clinical indication Radiation dose fractionation CTV definition N+ risk >20%
yes Midline tumour
<5x5cm field size 50Gy 16# No
e.g. T1 N0 glottis Bilat
Unilat
<6x6cm field size 55Gy 20#
Levels? Levels?
e.g. T2 N0 glottis Local RT to
primary site
NB: Manchester Experience of 55Gy in 20 fractions used for locally
advanced SCC HN as long as length of irradiated pharynx <8cm RT dose based Node pos elective Post-op
on field size
Choose appropriate dose and technique
Radiotherapy techniques I Wedged pair technique - parotid

• Minimises dose to
• Wedged pair techniques for lateralised CTVs
parotid, spinal cord,
– e.g. parotid, oral cavity, early tonsil lesions
oral cavity c/l
• Parallel-opposed lateral fields for midline CTVs mucosa and
– e.g. Larynx, hypopharynx, BOT, nasopharynx mandible
• Anterior/posterior fields for neck irradiation • Wedges used to
improve dose
homogeneity
Wedged pair technique – oral cavity Parallel opposed lateral fields

•Optimal for CTVs
•Suitable for buc anterior to spinal cord
mucosa, lateral tongue
•Adverse for mucosal
•Care with floor of irradiation c.f. Wedged
mouth, deeply pair technique
infiltrative tongue
tumours •En passant irradiation of
adjacent lymph nodes in
•Hot spots tend to occur level 3, probably not
in mandible clinically relevant

10:00am
Parallel opposed Parallel opposed fields

for pharyngeal tumours
lateral fields
• Irradiation of
mandible, parotid
glands, oral
cavity, spinal cord
• Always needs
modification of
fields after ~40-
44Gy
Parallel opposed fields for pharyngeal tumours Parallel opposed fields for pharyngeal tumours:
managing the match line
• Leaves level V and

posterior level II (IIb)
at 40-44Gy
• Need to use posterior
neck electrons to
cover this area
• Controversy
surrounding dose
required for elective
nodal irradiation: 44
vs 50Gy?
Parallel opposed fields for pharyngeal tumours:

managing the match line- importance of neck position
Anterior and posterior fields for
neck irradiation
RPNs
II II
Ib Ib
III
III
V
V IV IV

10:00am
Anterior and posterior fields : be Field matching

aware of what is under the block!
• Typically lateral fields are used to treat the
primary site for mid-line CTVs of the
pharynx and larynx
II • Bilateral split neck fields are matched
Ib
III below
V IV • Single isocentre techniques minimise field
overlap
T4 N0 Larynx SCC T4 N0 Larynx SCC

•Phase I: Asymmetric large lateral fields matched to an anterior
neck field with mid-line spinal cord shield. Dose 40Gy in 20
fractions
T4 N0 Larynx SCC
•Phase II
Practical processes of head
Reduced lateral field off cord
at40Gy
and neck radiotherapy
Match electrons to V for a
further 10 Gy (total 50 Gy)
planning
•Phase III
15 Gy boost to the larynx PTV

using parallel pair.

10:00am
Mould room
Mould room
Immobilisation shell Simulation
Treatment planning Radiotherapy planning
•Define field borders

•Outline through
centre of volume
•Define treatment
volume

10:00am
Radiotherapy planning Radiotherapy planning - conventional
•Anterior and •Dose coverage of

posterior wedged tumour
fields •Avoidance of spinal
cord and c/l parotid
gland
•NB irradiation of oral
cavity cerebellum and
ear
Linear accelerator Linear accelerator: Portal Imaging
Problems With Conventional RT

for Head and Neck Cancer I
Three-Dimensional Conformal
• Poor definition of target volume and normal
tissues in 3D Radiotherapy (3DCRT) for Head
• Inability to accurately determine doses to and Neck Cancer
tumour and normal tissues (prognostication)
• Inability to optimise radiotherapy for
individual patients to increase dose delivery
and minimise risk of complications

10:00am
CT Planning - Scan Acquisition

CT Planning - Tumour Localisation
in Three Dimensions
CT Plan - Planning Target Volume CT Planning - Volume Definition
Movement
+ uncertainty
margin
CT planning - 3D Reconstruction CT planning - 3D Reconstruction

10:00am
CT Planning - Beams-Eye-View CT Planning - dose calculation
CT Plan - 3D Plan Evaluation CT Plan - 3D Plan Evaluation
Tumour
Volume
of target
Normal tissue
Radiation Dose
3D Conformal Planning - Benefits

Site Author Benefits
Parotid Nutting 2000 Reduced dose to cochlea by 20%, Target volume definition in
oral cavity by 30%
Paranasal Adams 2001 Reduced optic nerve dose by
sinus 10%, parotid gland dose by 30%, head and neck cancer
potential to dose escalate
Nasopharynx Zelefsky 1998 Improved parapharyngeal space
coverage in T2b tumours
Oropharynx Eisbruch 1998 Reduced parotid gland irradiation
Thyroid Nutting 1999 Reduced normal tissue irradiation

by40%, spinal cord dose by 50%

10:00am
NODAL
Two components: OUTLINING
Patterns of spread documented in
1. NODAL OUTLINING large retrospective surgical series.
Robbins Lymph Node classification :

– Level Ia: submental triangle
2. PRIMARY TUMOUR OUTLINING – Level Ib: submandibular
triangle
– Level II: upper jugular
– Level III: mid jugular
– Level IV: lower jugular
– Level V: posterior cervical
triangle
– Level VI: anterior neck Sobotta, 1982
CONSENSUS OUTLINING GUIDELINES Level II – UPPER

Leve Cranial Caudal Anterior Posterior Lateral Medial
DEEP CERVICAL
l
NODES
Ia Mandible Hyoid bone Symphysis Body hyoid Ant. Belly of n.a.
menti bone digastric m.
Ib Cranial edge Hyoid bone Symphysis Post. edge Mandible, Lat. edge of
Anatomy:
SCM menti; SCM platysma, ant. belly DG • From carotid bifurcation
platysma skin
(hyoid) to skull base.
II Caudal edge Caudal edge SM,ICA,post Post edge Medial edge Med. edge
lat. process hyoid bone belly DG SCM SCM ICA,PS • Posterior border of the SCM to
C1 the lateral border of the
III Caudal edge Caudal edge Ant edge Post edge of Medial edge Med edge stylohyoid muscle
hyoid bone cricoid cart. SCM, postlat SCM SCM ICA,PSm
edge SH
IV Caudal edge 2cm cranial Ant edge Post edge of Medial edge Med edge – LEVEL IIa: anterior to the
cricoid cart to SCJ SCM SCM of SCM ICA, PS spinal accessory nerve
V Cranial edge Cervical Post edge Ant edge Platysma, PSm – LEVEL IIb: posterior to the
hyoid bone transverse SCM trapezius m skin spinal accessory nerve
vessels
VI Caudal edge Sternal Platysma, Between Thyroid gl., n. a.

thyroid manubrium skin trachea and skin, SCM
cartilage oesophagus
Sobotta, 1982
Gregoire et al 2002
Level II: Caudal edge lateral process C1 to caudal edge hyoid bone
Level IIa: post border- ant edge SCM
Level III – MIDDLE
SM gland, ICA, post belly Digastric JUGULAR NODES
Anatomy:
medial edge ICA, PSm

medial edge SCM
medial edge SCM
• From carotid bifurcation

(hyoid) to the junction of the
omohyoid muscle with the
IJV(cricoid level).
• Posterior border of the SCM to

the sternohyoid muscle
Sobotta, 1982
post edge SCM

10:00am
Level III: Caudal edge hyoid bone -- caudal edge cricoid cartilage
Level IV– LOWER
Ant edge SCM , posterolateral edge Sternohyoid JUGULAR NODES
Anatomy:
medial edge SCM

medial edge SCM
• From the junction of the

IJV(cricoid level) to the
clavicle.
• Posterior border of the SCM

to the lateral border of the
sternohyoid muscle
post edge SCM Sobotta, 1982
Level IV: Caudal edge cricoid cartilage -- 2cm cranial to SCJ

Level V– POSTERIOR
TRIANGLE NODES
Ant edge SCM m
Boundaries:
medial edge SCM
• Anterior border of the

medial edge SCM
trapezius muscle to
Posterior border of SCM
• Skull base to Clavicle
It includes the
supraclavicular nodes
post edge SCM Sobotta, 1982
Level V: Cranial edge hyoid bone to Transverse cervical vessels Level V: Cranial edge hyoid bone to Transverse cervical vessels
Post edge SCM Post edge SCM

Platysma
Platysma
PSm
PSm
Platysma
PSm
Platysma
PSm
anterior edge trapezius m.

Anterior edge trapezius m.

10:00am
Level V: Cranial edge hyoid bone to Transverse cervical vessels
Post edge SCM PRIMARY TUMOUR OUTLINING
• NO ACCEPTED GUIDELINES
• Sources of information:
PSm
– Tumour site/ stage
– Tumour natural history
Platysma
– Anatomical descriptions
– Surgical experience
– Lessons from conventional radiotherapy
anterior edge trapezius muscle
PRIMARY TUMOUR
OUTLINING
• GTV: Gross Tumour Volume (CT/MRI,
EUA, clinical examination, PETCT)
The End!
• CTV (customised) = GTV+1-2cm margin
• Edited out of air, skin, bone (if no risk
of involvement)
• Edited to encompass entire organ when
indicated
• PTV= CTV+ 3mm margin

10:45am
Technology Timeline
Implementation
CRT IMRT VMAT
Helen McNair
Research Radiographer Port Electronic IGRT Improved

Film Portal Imaging Immobilisation
Royal Marsden Foundation Trust

and Institute of Cancer Research
Technology Timeline IMRT Implementation
How?
CRT IMRT VMAT
Port
Film
Electronic
Portal Imaging
IGRT Improved
Immobilisation Site? Trial? Patient?
Site - all patients in that site? Key Team

Maintain Quality
Trials - “data on health care and resource use
and clinical effectiveness observed in a routine Clinician
care environment. The new treatment should be
compared to the most common existing Implement Agree
treatment approach” changes protocols
Hutton and Maynard, Health Econ 9: 89-93 (2000)
Patient - how can resource it?

Review process

10:45am
Training Changes in working practice
Higher monitor units
Teaching Unable to check - ‘not intuitive’
MLC
Practical sessions
Time constraints
Dummy rums
Verification
Immobilisation
Reproducibility Reproducibility
Rethink position
Evaluate accuracy
Thermoplastic mask systems

Thermoplastic shell
4 or 5 fixation points
Posicast 4 /5 point fixation Mask shrinkage

“S” type
1.5 ± 0.3mm during day 1
Maximum 0.5 mm over next 3 days
Cantilever board with shoulder

Tsai et al 1999
depression
Gilbeau et al 2001
Images courtesy of Oncology Imaging systems and Oncology Systems Ltd

10:45am
Thermoplastic shell Couch attachment
Reproducibility Reproducibility
Skill of the maker/operator
Support system
Patient
Stereotactic Frame Stereotactic Frame
97% vectors < 2.5mm
performance status
dentition
Burton et al, 2002 , Clin Oncol

10:45am
CT Scanning
Limitations
Pt changes after making Conformal therapy

shell
Levels
Pt changes through Contrast

course of treatment
Planning Verification
Head and Neck
Outlining
1/2 hr Conventional
1 1/2 hr IMRT
TLDs Ion Chamber Film
Dosimetry Time ~ 4-5 hrs

3 hrs Conventional
4.5 hrs IMRT
Delta 4 Time ~ 1.5 hrs
phantom
Allow a week SCOR January 2010
Planning Resources Treatment Delivery
Head and Neck IMRT and Conventional treatment times

20
18
Clinician outlining,
QA, 2.5 2.3 16
Time (mins)
14
12
10
8
Radiographer, 2.4
6
0
Dosimetry, 5.8
single 1 2 3 all phases
IMRT HNC Conventional HNC
Technique
Courtesy of Liz Miles Data courtesy of Liz Miles

10:45am
Patient and Fluence Verification Planning issues

Large field sizes
Orthogonal films, protocols
Validation Day 1 Day 14

Films or EPI
Conclusion
Immobilisation AND reproducibility
Dummy runs
Staff training
Evaluate treatments

11:45am
Learning objectives
Cross sectional imaging in the  Role of imaging in the decision making
process of the patient with head and
evaluation and staging of neck cancer (laryngeal and pharyngeal
cancer)
head and neck cancer  Resectable vs. unresectable
 Importance of paraglottic and pre-
pre-
Julie Olliff epiglottic spaces
 Transglottic spread
University Hospital  Laryngeal cartilage invasion
Birmingham  Metastatic disease
 Nodal
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP  pulmonary
Treatment choice Radiotherapy or surgery?

 Palliation or cure?  Early stage T1/2 little evidence to suggest any
advantage between RT and organ preserving
 Medical therapy or surgery surgery (beware anterior com involvement)
 Resectable or unresectable
 T3/4 chemo-
chemo-radiation preferred
 Unresectable does not necessarily
 Laryngeal cartilage invasion
imply incurable
 Poor control by radiotherapy with increased risk of
 T4a and T4b late complications but studies performed with older
 Vascular encasement and invasion CT scanners. Not necessarily associated with poor
control.
 Prevertebral space invasion  Laryngeal cartilage invasion used to be considered
 Invasion of mediastinal structures contraindication to RT and partial laryngectomy
Staging the primary tumour How can imaging help the clinician
 Mucosal extension better assessed by  Sub-

Sub-mucosal extension
endoscopy  Paraglottic disease volume affects response
to radiotherapy
 CT/MRI will not detect the majority of  Unexpected sub-
sub-mucosal extension
lesions confined to the mucosa  Anterior commisure
 Deep extension is better assessed by cross  Laryngeal cartilage invasion
sectional imaging  T4a and T4b
 Unsuspected nodal disease not covered
 CT/MRI will upstage the primary tumour in by standard treatment
approx. 25%  Metastatic spread

11:45am
Paraglottic and pre-

pre-epiglottic
Laryngeal cartilage invasion
spaces
Paraglottic  Ossified cartilage more susceptible
 Paired fatty regions  Three phases: inflammatory change within
beneath the true and cartilage adjacent to tumour inducing new
false cords
bone formation prior to actual tumour
 Merge superiorly into invasion, osteolysis,
osteolysis, frank invasion
the pre-
pre-epiglottic
space
Laryngeal cartilage invasion Laryngeal cartilage invasion

Diagnostic criteria CT – thyroid (111)
Diagnostic difficulties  Extra-
Extra-laryngeal tumour, sclerosis and erosion or
 Variable cartilage ossification lysis
 Tumour itself has similar attenuation values to Sens 94%, Spec 38%
non-
non-ossified cartilage but may cause new bone PPV 54%, NPV 89%
formation  Extra-
Extra-laryngeal tumour and erosion or lysis
 High signal on MRI may be due to tumour or to Sens 71%, Spec 83%
non neoplastic inflammatory change
PPV 76%, NPV 79%
Becker et al 1997
Laryngeal cartilage invasion Laryngeal cartilage invasion -MRI

 T2 W hyaline cartilage invaded by
Diagnostic criteria CT – all (111) tumour displays a higher SI
 Extra-
Extra-laryngeal tumour and erosion or  T1W invaded hyaline cartilage and fatty
lysis,
lysis, thyroid, arytenoid,
arytenoid, cricoid marrow display a low to intermediate
SI, peritumoural inflammatory change
 Sclerosis in the cricoid and arytenoid
may enhance, this is most commonly
Sens 82%, Spec 79% seen in the thyroid cartilage reducing
NPV 91% specificity to 56% rather than cricoid
and arytenoid 87% and 95%
 PPV 68-
68-71%, NPV 92-
92-96%
Becker et al 1997
Becker M EJR 2000; 33:216-229

11:45am
Laryngeal cartilage invasion
 T2 weighted or post contrast T1W

cartilage SI greater than that of adjacent
tumour = inflammation, SI similar to that
Neoplastic invasion
of adjacent tumour = neoplastic invasion
 Specificity all 82% (74%), specificity for
thyroid cartilage 75% (54%)
Becker M Radiology 2008; 249:551

T-staging of hypopharyngeal
cancer
T1 limited to one subsite and <=2cm in
max. dimension
Inflammation of thyroid cartilage T2 >one subsite or an adjacent subsite or
measures >2cms
T3 >4cms
T4 invades adjacent structures eg.thyroid,
eg.thyroid,
cricoid cartilage, carotid artery, soft tissues
of neck, pre-
pre-vertebral fascia/muscle,
thyroid, oesophagus
Subsites: piriform sinus, post hypoph wall, postcricoid
T staging of supraglottic
cancer
T-staging of glottic cancer
T1 tumour limited to one subsite T1 Tumour limited to vocal cord
T2 invasion of >one adjacent subsite of T2 Extension into supra/sub glottis
supraglottis,
supraglottis, glottis or region outside of supraglottis
T3 invasion of post cricoid area, pre-
pre- T3 Invasion of paraglottic space and/or minor
epiglottic/paraglottic space and/or minor thyroid thyroid cartilage erosion
cartilage erosion T4 Extralaryngeal tumour spread
T4 extra-
extra-laryngeal spread
T4a through thyroid cartilage or tissues beyond T4a Through thyroid cartilage or tissues beyond
eg.Trachea,
eg.Trachea, soft tissues of neck larynx eg.
eg. trachea, strap muscles, thyroid
T4b prevertebral space, mediastinum,
mediastinum, carotid T4b prevertebral space, mediastinum,
mediastinum, encasement
carotid artery
Subsites:
Subsites: mucosa of base of tongue, vallecula,
vallecula, medial wall of
pyriform sinus

11:45am
Radiotherapy or surgery? Resectability issues

 Limitations in current T staging system re
organ conservation therapy or not  Vascular encasement
 Tumour volume
 T1-
T1-T4 supra glottic <= 6ml 83% local control, >6ml  CT overestimates
43% (Mancuso et al 1999)
 T3 glottic <= 3.5ml 85%local control, >3.5ml 22%
 US with transcranial Doppler to determine
local control (Parmeijer
(Parmeijer et al 1997) crossflow
 Hypopharyngeal cancer >6.5ml poor response, also
tumour >1cm at level of pyriform sinus (Parmeijer
(Parmeijer et  MR >270deg. involvement accurate in
al 1998)
prediction of inability of surgeon to peel
 High risk profile
 Large tumour volume tumour off vessel
 Deep tumour spread
Prevertebral fascia involvement Mediastinal invasion

 Preservation of fat stripe. Variable width.
 Imaging has poor positive predictive value  Little evidence
 Loss of fat stripe, nodularity within
prevertebral muscle, abnormal T2, abnormal
enhancment – even if all four signs are
present 4/7 patients had no prevertebral
muscle infiltration when evaluated at surgery
(Loevner et al 1998)
Pulmonary metastases
Why image neck nodes?
 Already staging primary  Lung metastases is the most common site
 To identify nodes not clinically evaluable – of distant metastases in head and neck SCC
retropharyngeal nodes, difficult necks  The management of isolated non-
non-
 Surgical decision making significant lung nodules (defined as
 Bilateral disease subcentimetre nodules) is been much
Contra-
Contra-lateral disease
debated, with PET scanning, computer

 Nodal size
 Advanced disease aided diagnosis and video assisted
 Vascular encasement thoracoscopy (VATS) being suggested to
Skull base involvement

guide diagnosis
 To identify bulky nodal disease not treatable by
primary radiotherapy

11:45am
Conclusion
 Lung nodules (unlikely to represent Role of imaging
metastases) are common in head and  Paraglottic spread
 Volume
neck scc (14.6%)
 Extent
 12% of these developed lung cancer  Laryngeal cartilage invasion
 Options for management of these  Extra-
Extra-laryngeal extension
nodules include repeat CT scan at 6-6-12  Nodal and pulmonary status
 Unilateral / bilateral, volume, adverse features
months to assess for progression, PET
 Significant pulmonary nodule
scan or biopsy (either radiologically or
by VATS)
 497 CT scans reviewed

 187 with head and neck scc
 16 excluded (11 duplicates and 5 had no notes
available)
 25 patients with non-
non-significant lung nodules
 3 of these malignant
 27 patients with significant lung nodules
 24 malignant
 3 patients with a normal CT scan on screening
developed lung cancer at later date

12:30pm
Steps in Inverse-
Inverse-planned IMRT
1. Define clinical dose specifications

IMRT treatment planning 2. Delineate contours
basics 3. Select isocentre and beam orientation
4. Define optimisation parameters and
Dr Catharine Clark priority factors
5. Optimise plan
6. Convert fluences to leaf motions
7. Calculate
8. Analysis
Define clinical dose specifications Define clinical dose specifications
 Dose prescription  Dose constraints

 Primary target dose and fractionation  Organs at Risk
 Secondary (elective target) dose and – Spinal cord, brainstem
fractionatation – Parotid glands
 Decide what these doses are prescribed to  Volumes of interest
– Isocentre – Larynx region
– Volume – Oral cavity
– Isodose line
Define clinical dose specifications Delineate contours
a specification of the acceptable doses to be full 3D outlining of the volumes

delivered to or avoided by those volumes
Targets have a minimum

and maximum dose value.
OARs have a maximum

allowed dose and
sometimes other
volume/dose limits
Including all volumes of (any) interest

12:30pm
Selecting beam parameters

 Isocentre position  MLCs have physical limitations e.g.
– Can affect field splitting and MUs – Minimum leaf separation
 How many beams? – Maximum over-
over-travel
 Beam directions? These need to be accounted for by the TPS
• equispaced?
equispaced?
• non-
non-coplanar?
 Selection of planning parameters may
minimise problems
• need to consider set-
set-up limitations
– Gantry angle
 Collimator angles? – Collimator angle
• may need to consider MLC limitations
– Isocentre position

Optimisation parameters
• Equispaced fields may not be the most practical

3 different dose-volume sets
• Avoid treating through unnecessary tissue
• Need to consider potential collisions and avoid 1. Clinicians goals
beams passing through the couch and 2. Planning parameters
immobilisation systems 3. Final dose distribution
• Adjust gantry and collimator rotations
Need to know how to interpret one
• Small adjustments not so critical to plan result as into another
can often be taken into account by fluence
Optimisation parameters Optimisation parameters

Planner describes Planning system Evaluate  Avoid conflicting requests
problem develops plan plan
– Where structures overlap, decide
Unacceptable Acceptable
beforehand what you want the
Planner changes how
compromise to be
he describes problem – Don’
Don’t ask for dose in impossible places
(e.g. build-
build-up region)
FINISH !! – Be realistic

12:30pm
Optimise the plan

Optimisation parameters
 May need to set tighter constraints than
actually required
 System allows interaction with constraints as
optimisation proceeds
– can start with relaxed constraints and tighten as
necessary
 Beware of unattainable constraints, e.g.
– maximum dose of 40Gy in an OAR which overlaps
a PTV with a minimum dose of 60Gy
– high dose required in build-
build-up region
Optimisation and delivery Delivery considerations

Planner describes Planning system Evaluate  Delivery sequence generated after
problem develops plan plan
optimisation
Unacceptable Acceptable  How the fluence is actually delivered will
Planner changes how affect the dose distribution
he describes problem
– head scatter
Unacceptable
– transmission / leakage
Make Evaluate Generate deliverable
adjustments plan plan – (tongue-
(tongue-and-
and-groove)
Acceptable
FINISH !!
Conversion options
Plan normalisation
 IMRT plans may not have the isocentre
in an appropriate position for
normalisation
 IMRT plans may have non-
non-uniform dose
across the target => normalisation
point may be in slightly hot/cold region
 Often better to normalise to the mean
or median target dose

12:30pm
Class solutions Class solutions
 Determined from planning studies of a  no. of beams

group of patients – e.g. 5 or 7
 beam energy
 Give a set of starting parameters for the – e.g. 6MV
optimisation, which will generally meet  beam directions & collimator angles
the plan requirements – e.g. equispaced or set angles
 starting dose-
dose-volume constraints
5 field class solution

Example: H&N IMRT plan
 Difficult to deliver radical radiotherapy due to
Anterior (0°)
complex anatomy; spinal cord (which is RAO
susceptible to radiation damage) sits within LAO
(300°) (60°)
concavity in target volume
 Clinical trial of IMRT

commenced:
• PTV1 receives 65Gy in 30 #
• PTV2 receives 54Gy in 30 # RPO LPO
(240°) (120°)
User works with

the constraints
Initial dose constraints and priorities to
guide the
system towards
Planning DVH
the optimal
points are set for
each of the organs. solution
Targets have a
minimum and
maximum dose Optimisation
value. stops when
maximum
OARs have a number of
minimum dose of
0Gy and a
iterations
maximum reached or user
allowed dose chooses to stop

12:30pm
Leaf Motion Calculator 5 field class solution

The conversion of the ‘optimal’ fluence to the‘actual’ Anterior (0°)
fluence takes into account the characteristics of the MLCs RAO LAO
(300°) (60°)
• Transmission • Available leaf speeds

• Rounded shape of leaf ends • Maximum field width RPO LPO
• Dose rate (240°) (120°)
DVH calculated from actual fluences

Dose distributions
PTV
normalised
to 50% vol
at 65 Gy
95% isodose 78.9% isodose
Summary
 It is important to perform planning studies
prior to clinical implementation
• demonstration of expected benefits
• familiarisation with planning methods
• assessment of practicality
• development of ‘class solutions’
solutions’
• establish clinical trial protocols

Day 1 Session 3 Practical Session
2:00pm
What is the parapharyngeal space
 Central fat filled spaces in lateral supra-

supra-hyoid
The parapharyngeal space neck with important spaces around them
 Contents
 Fat, minor salivary glands, internal maxillary artery,
ascending pharyngeal artery, pterygoid venous plexus
Julie Olliff
 Surrounding spaces
University Hospital  Pharyngeal mucosal space, masticator space, parotid
Birmingham space, carotid space, lateral retropharyngeal space
UK
 No fascia separates inferior PPS from posterior
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP submandibular space
What are the parapharyngeal

spaces? Anatomy
Central fat filled spaces in lateral supra-
supra-hyoid neck with
important spaces around them
Masticator
space
Parotid Parapharyngeal Pharyngeal

space space Mucosal space
Carotid
space
How to image How to report

 MRI generally preferred for supra-
supra-hyoid  Determine anatomical site of origin using pattern
of displacement of PPS fat and position of
neck internal carotid artery – remember most lesions
 Axial T1SE – good for anatomy and flow of PPS arise from adjacent supra-
supra-hyoid neck
voids spaces
 Remember anatomical contents of each space to
 Axial T2 SE, STIR – good for morphology form differential diagnosis
 Post contrast T1 – enhancement  Narrow differential diagnosis
characteristics (care over timing)  Clinical history
 Morphology eg.eg. Pattern of contrast enhancment
 CT for skull base involvement  Frequency of condition

2:00pm
Anatomy – parotid space Mass – parotid space

 Pleomorphic
adenoma
 Warthin tumour
 Mucoepidermoid
 Adenocystic Ca
 Metastasis –SCC,
melanoma
 Branchogenic
anomaly
Parotid space-
space- stylo-
stylo-mandibular Anatomy – masticator space
tunnel
Mass - masticator space Carotid space

 Odontogenic
abscess
 Malignant
tumour – NHL,
sarcoma, SCC
from retromolar
trigone,
trigone,
rhabdomyosarco
ma (paediatric)

2:00pm
Mass - Carotid space Lateral retropharyngeal space

 IJV thrombosis
 ICA thrombosis,
dissection,
aneurysm etc.
 Paraganglioma:glo
mus jugulare,
jugulare,
vagale,
vagale, carotid
body tumour
 Nerve sheath
tumour:
schwannoma
 Lymph node met
Lateral retropharyngeal space

Pharyngeal mucosal space
 Lymphadenopathy
reactive,
reactive, inflam,
inflam,  Adenoidal/tonsillar
Adenoidal/tonsillar
suppurative,
suppurative, inflammation,
malignant (SCC, abscess
NHL, melanoma,  Juvenile
thyroid) angiofibroma
 Direct invasion  SCC
from primary SCC  NHL
esp. posterior wall
True lesions of parapharyngeal fat

Position of ICA
space
 Parotid and extra-
extra-parotid salivary gland  Salivary gland tumours
tumours displace ICA posteriorly  Parotid gland migrates embryologically from
 Paragangliomas and most schwannomas pharyngeal wall and may leave ectopic
salivary tissue in parapharyngeal space
displace ICA anteriorly
 Neurogenic tumours – schwannoma from
sympathetic chain (rare)

2:00pm
Non visualisation fat between mass

Schwannoma vs paraganglioma
and parotid
 Tumour of parotid origin (80%)  Paraganglioma - high velocity flow voids on
unenhanced T1scans
 Large extra-
extra-parotid tumour  Paraganglioma - hypervascular on early phase
with wash out
 Tumour adherent to parotid capsule
 Carotid body paraganglioma may splay ICA/ECA
 Tumour invasive (rare)  Schwannoma hypovascular but may show
enhancement on delayed scans post IV contrast
 Involvement of skull base
 Schwannomas –smooth and well defined
 Paragangliomas – shaggy appearing margins
Infection Conclusion
 Most arise in other spaces and extend into  Look for the position of the fat
parapharyngeal space – odontogenic,
odontogenic,  Look for the position of the ICA
pharyngeal, otogenic
 Complications  Morphology of mass
 IJV thrombosis  Remember the contents of the spaces and
 Carotid artery aneurysm and rupture the common pathologies
 Mediastinitis
 Meningitis

2:00pm
Romania 2010
Functional imaging
 Advantages
 Identifies metabolically active tissue
 Depends on activity not size
 Whole body imaging technique
 Assess treatment response prior to size
change
 Post treatment anatomic distortion less
PET/CT in lung & oesophageal cancer significant
Sheila Rankin
 Quantitative measurements – SUV
Guy’s & St Thomas’
SUV = FDGregion/FDGdose Body Wt
London UK
Lung Cancer
>380,000 new cases/year in EU
Commonest cause of cancer death
PET/CT in lung 80% NSCLC
cancer Poor overall survival
 1 year survival 25%
 5 year survival 7 - 15%
 Stage 1 60-
60-80%
 Stage 1V 1.6 -2%
 20-
20-30% eligible for surgery
False positives
FDG-
FDG-PET in nodules T1
Granulomas
 SUV > 2.5 Abscess
Sensitivity 94% Sarcoid
Specificity 71% Amyloid
Accuracy 86% Wegener’s
PPV 90% Rheumatoid
NPV 85%
Histoplasmosis
Aspergillosis

2:00pm
False negatives
Bronchoalveolar cell
carcinoma
Carcinoid
Tumours < 1cm
FDG PET in T1 tumours T definitions - T3

Tumour any size that
 FDG PET vs CT nodules < 3cm invades
 136 nodules 81 malignant 55 benign  Chest wall (superior
sulcus)
 <1cm all negative on PET (8- (8-M, 12-
12-B)
 Diaphragm
 1-3 cm 15 FN, 15 FP (73-
(73-M, 43-
43-B)
 Mediastinal pleura
 Sensitivity 79%, specificity 65%  Parietal pericardium
 Solid nodules sens 90%, spec 71%  Tumour < 2cm from
 Ground glass sens 10%, spec 20% carina
Nomori Lung Cancer 2004:45  Nodules in same lobe
 Tumours > 7cm
T definitions – T4
Tumour any size that
invades
 Mediastinum
 Heart, great vessels
 Carina, trachea,
oesophagus
 Vertebral body
 Nodules in different
lobe, ipsilateral lung PET/CT more accurate than CE CT for T
stage 86% vs 79%
Shim Radiology 2005

2:00pm
Prognosis SUV - prognosis

 Lung cancer
 SUV <5.5 14% recur
 SUV > 5.5 37% recur
 Goodgame J Thor Onc 2008
 SUV < 9 2 year survival 96%

 SUV > 9 2 year survival 68%
 Downey JCO 2006
 SUV > 20 median survival < 6 months

 Dhital 2000
Davies A et al Lung Cancer 2007
N2 – ipsilateral mediastinal &subcarinal nodes

N1 – nodes removable at pneumonectomy/lobectomy
False Positives
TB Histoplasmosis PET and CT
similar
Sarcoid COPD Ebihara Jpn JCO
2006
Anthracosis
N3 – contralateral/supraclavicular nodes
SUV 2.5 often used

SUV 5.3 Accuracy for malignancy 92%
Bryant Ann Thorac Surg 2006

2:00pm
N Stage - accuracy
Author No: CT PET PET/CT
Cost effectiveness of mediastinsocopy
Cerfolio 400 68% 76%  Clinical Stage 1 (CT and PET)
2003
Cerfolio
 Unsuspected N2 disease in 5.9%
129 56% 78%
2004  Benign nodules 8%
93%
Use SUV 5.3  Mediastinoscopy added 0.008 years life
Malek 170 78% 74% expectancy
2008  Cost $250,989 per life-
life-year gained
Yang 122 70% 85%  If prevalence of N2 disease >10%
2008
 Cost $100,000 per life-
life-year gained
de Wever 50 60% 70% 80% Meyers J Thorac Cardiovasc Surg 2006
2007
Nodal staging
FDG - PET in Lung cancer
PET/CT EUS Mediastinoscopy
Distant metastases are common in up to 20%
N0 N2 in 3.7% N2 in 2.9%
of patients
N1 N2 in 23.5% N2 in 17.6%
If N0 on PET, occult N2 more likely if
100 patients unsuspected metastases
SUV > 10, Adenocarcinoma, RUL (10% N2)
6 (9%) of 69 with N0/N1 disease
Mediastinoscopy in this group or N1, not N0
7 (28%) of 25 with N2 disease
Cerfolio Chest 2006
6 (100%) of 6 with N3 disease
PET/CT EBUS No false positives
N0 N2 in 6% Weder.
Weder. Ann Thoracic Surg.1998.66:886
Herth Chest 2008
PPV 98% if both +ve

PPV 61% if PET +ve
only
PPV 17% if PET -ve

2:00pm
Staging of NSCLC FDG-

FDG-PET in restaging after
CT PET PET/CT induction therapy
Tumour 68% 46% 86%  54 patients post CRT
Nodes 66% 70% 80% Primary Nodes
Metastases 88% 96% 98%  Sensitivity 94.5% 77%
TNM 46% 30% 70%  Specificity 80% 68%
Overstage T 20% 16% 8%  Accuracy 91% 73%
Understage T 12% 38% 6%  Negative PET (SUV < 2.5) or SUV >80%
Overstage N 28% 20% 16% predict a favourable outcome, if <25% 5yr
Understage N 6% 10% 4% survival 5%
De Wever Eur Radiol 2006 Eschmann Eur J Nuc Med Mol Imag 2007
Restaging N2 disease
CT 60%
Recurrence following surgery
 Recurrence rate 37.5 - 50%
PET-CT 83%
 90% within 2 years
Mediastinoscopy 60%  Loco-
Loco-regional 23 - 40%
(sensitivity 29%)  Distant 66 - 74%
De Leyn J Clin Onc 2006  Loco-
Loco-regional+Distant 9.5 - 14%
Limitations  Overall AdenoCa > SCC
Nodes FP 25%  Pneumonectomy 54%, lobectomy 34%
FN 20% Jang. J Thor Imag 2003
Walsh Ann Thor Surg 1995
Bx if still metabolically active
Cerfolio. J Thorac & Cardio Surgery 2006
Bronchial stump recurrence 15-44%

Wedge > radical surgery (79% vs
34%)

2:00pm
2005 2007
Role of PET/CT in Lung Cancer
 Conclusions PET/CT in
 Use in patients with stage 1 or 11 disease to
further stage the patient prior to surgery Oesophageal cancer
 Use prior to radical radiotherapy and for RT
planning
Dr S C Rankin
 Use for minimal N2 disease if surgery an option
 Assessment post induction chemo-

Guy’
Guy’s & St Thomas’
Thomas’ Foundation Trust,
chemo-RT
London
 Suspected recurrent disease
Oesophageal cancer Oesophageal cancer

SCC Incidence
 Associated head & neck cancer, smoking, SCC
alcohol, HPV, achalasia  5-10/100,00 in west. 100/100,000 in east
 Male, lower socio-

socio-economic group Adenocarcinoma
 commoner in west than SCC. 5- 5-12/100,000.
 mid oesophagus (75%)
Increased 400-
400-800% since 1970
Adenocarcinoma
Prognosis
 Barretts,
Barretts, G-
G-O reflux  Tumour lethality rate of 0.95
 Male, upper socio-
socio-economic group  If operable 5-
5-20% survival
 Distal third (94%)  Most inoperable treated with chemoRT

2:00pm
Primary Tumour (T) T Stage

T0 No evidence of
primary tumour Benign uptake in oesophagitis
Tis Carcinoma in situ Sensitivity for primary 63-95%
T1 Tumour confined
to mucosa or invades High in SCC
lamina propria or Low uptake in 20% of adenoCa
submucosa
T2 Tumour invades • diffuse
muscularis propria • poorly differentiated
T3 Tumour invades
adventitia • mucus containing tumours
T4 Tumour invades
T1
adjacent structures
PET/CT in differentiation benign N stage

from malignant lesions
Malignant
 Eccentricity (Tis
(Tis,, T1, T2)
 Focal (Tis
(Tis,, T1, T2)
Sensitivity 83.3%, specificity
68.2% for malignancy T2 eccentric
 SUV > 3 (only useful in T2, not T1
and Tis)
Tis) in differentiation from benign
lesions
Roedl.
Roedl. AJR 2008
Sensitivity 51%
N stage M stage – FDG-PET
Specificity 84%
False negative
• Small nodes
• Close to primary
False positives
• Inflammation
• Anthracosis Accuracy 72-88%
• Sarcoid Liberale 2004 EJSO
Sihvo 2004 J Gastrointest Surg
Van Westreenen J CO
2006

2:00pm
Prognosis – oesophageal cancer Neoadjuvent chemotherapy

Low survival time
 Positive nodes on FDG-
Chemotherapy + surgery
FDG-
PET pre chemo  Complete resection in 60%
 Number of positive nodes  Median survival 16.8 months
 Tumour length on FDG-FDG-  2 year survival 43%
PET
Surgery only
 SUV. Higher the SUV –
poorly differentiated  Complete resection 54%
tumours  Median survival 13.3%
 4 year survival SUV < 6.6
 2 year survival 34%
89%, > 6.6 31% MRC OE-
OE-02 (2002)
Cerfolio Ann Thor Sug 2006
Oesophageal cancer Neo-

Neo-adjuvent chemoRT
 Locally advanced disease
 15-
15-19% non responders or progress
 Median survival 3-3-5 months
 No benefit from therapy
 5 year survival following resection 10-
10-35%
 Toxicity
 Chemo-
Chemo-radiotherapy used
 Surgical delays so inappropriate
 To downstage tumour
 Survival worse than patients who undergo
 Improve complete resection rate
surgery alone
 Improve 3 year survival  Greater post op morbidity/mortality
 Eradicate microscopic metastases
 Change of therapy
 Reduce locoregional recurrence
Urschel Am J Surg 2003
Using a reduction
Response assessment of > 50% in
maximal cross
 Early sectional area
After 1 week of induction therapy Sensitivity 87%
to assess responsiveness Responder
PPV 80%
 Late
After completion of induction therapy to
assess residual disease and provide
prognostic information
Non responder
Chak. Cancer 2000

2:00pm
pre
Volumetric method PET/CT in response to therapy
2 weeks after chemotherapy
 Change in metabolic activity precedes
Reduction of 14.8%
anatomic change
Predict histologic response
with 100% sensitivity, 53% post
specificity
No correlation between
tumour reduction and
progression free survival
-10% -30%
Beer Radiology 2006
Early response on PET FDG at 14 days and

completion of therapy
 14 days post chemotherapy No correlation at 14 days
 SUV reduction of 35% between decreased FDG
 Responders more chemo then surgery, uptake and tumour size on
 Non Responders surgery CT, did correlate at end of
 Follow up median 2.3 years therapy
Path Resp median overall survival EFS Change in activity at 14 days
(<10% cells) more specific for response
Responders 58% not reached 29/12 that at completion of therapy
Non responders 0% 25/12 14/12
Wieder J Nuc Med 2005
MUNICON trial Lancet Oncol 2007
Wieder JCO 2004
Response to therapy
Re-
Re-staging post chemo/RT
Criteria for non responders
 CT wall thickness > 14.5 mm Accuracy T4 vsT1-
vsT1-3 Nodes
 EUS tumour length > 1cm
 PET SUV > 4 CT 76% 78%
PET CT EUS EUS/FNA 80% 78%
FDG-
FDG-PET/CT 80% 93%
Accuracy 76% 62% 68%
None can differentiate complete response from Complete Response accuracy
microscopic (<10% cells) disease
CT 71%
Only SUV > 4 independent predictor of survival (2 yr EUS 67%
survival 34 vs 64%) FDG-
FDG-PET/CT 89%
Swisher Ann Thor Surg 2004 Cerfolio 2005 J Thorac Cardiovasc Surgery

2:00pm
Recurrent disease Sites of recurrence

 Recurrence rate  Locoregional
 34-
34-79% - Mediastinal nodes, anastomosis
 Higher initial T and N stage  Distant
 50% in first year, most within 2 years  Abdominal nodes
 30% in operative field  Lung
PM study  Liver
 63% had disease following curative surgery  Pleura
 43% who died from other causes had  Adrenal
recurrent disease
Sites of recurrence
Conclusion
 Less common – cervical nodes,
peritoneum, bone
 FDG-
FDG-PET provides more information
about response to therapy and prognosis
EUS/CT PET
 PET and CT similar for recurrent disease
Sensitivity 89% 96%  Use FDG-
FDG-PET for problem solving
Specificity 79% 68%  Surgical distortion
Accuracy 84% 82%  Rising markers

4:00pm
Cochrane Shanks/Jalil Travelling Professorship Overview

Cluj-Napoca, Romania
June 2010 • Context of 5 Rs of radiobiology and 6 hallmarks of
cancer
Interfaces Between Classical and
• Molecular mechanisms of tumour repopulation and
Molecular Radiobiology
targeted therapy approaches
Dr Kevin Harrington PhD FRCP FRCR • Reoxygenation as a therapeutic target
Reader in Biological Cancer Therapies • DNA repair and the potential to modulate it for
therapeutic gain
• Genetic analysis of the difference between sensitive
and resistant tumours
Frameworks of Classical and Molecular Radiobiology Tumour Repopulation
The 5 Rs of Radiobiology The Hallmarks of Cancer

Response to injury
Tumour growth rate
Depletion of tumour cells improves

nutrient delivery to survivors
• Repopulation
Dog-leg curve Darwinian selection – surviving cells
• Repair grow faster
• Reoxygenation
10 20 30
• Redistribution Time from start of treatment (days)
• Radiosensitivity
Withers Adv Radiat Biol. 1975; 5: 241-7

Steel et al. Int. J. Radiat. Biol. 1989;56: 1045-8 Hanahan and Weinberg 2000
Altered Fractionation in Response to Accelerated Repopulation ErbB-receptor family and its ligands
EGF
Conventional fractionation NRG2
TGF
Amphiregulin NRG3
HB-EGF Heregulins
?
Hyperfractionation Epiregulin
Heregulins -cellulin
Accelerated hyperfractionation
Cysteine-rich
domains
Concomitant boost
Split-course accelerated Tyrosine kinase

hyperfractionation domain
C-terminus
ErbB-
ErbB-1 ErbB-
ErbB-2 ErbB-
ErbB-3 ErbB-
ErbB-4
CHART Her1 Her2 Her3 Her4
EGFR neu

4:00pm
Activation of transmembrane tyrosine kinase receptors EGFR as an archetypal growth factor receptor
EGF - + R R -IR +2Gy

ligand binding dimerization ligand binding
P-EGFR RAS RAF
P-EGFR
PI3-K pY
K K SOS
pY
extracellular ligand GRB2
pY
binding domain MEK
STAT
PTEN AKT
transmembrane MAPK
domain
P P proliferation/ Gene transcription

Tyr Tyr Tyr Tyr
Tyr P Tyr Tyr P Tyr maturation Cell cycle progression
P P myc cyclin D1 Cyclin D1
P Tyr P intracellular tyrosine DNA
Tyr Tyr Tyr Jun Fos
kinase domain
Myc metastasis
Tyr P Tyr Tyr P Tyr
Survival / anti-apoptosis angiogenesis
Tyr P Tyr Tyr P Tyr
activation of signaling cascades
EGFR overexpression in human tumors Potential Effects of EGFR Blockade
Tumours showing high

EGFR expression
• NSCLC 40-80% • Repopulation
High expression generally
• Prostate 40-80% associated with • Repair
• Gastric 33-74% • Invasion
• Breast 14-91% • Metastasis
• Reoxygenation
• Colorectal 25-77% • Late-stage disease • Redistribution
• Pancreatic 30-50% • Chemo-/Radiotherapy
• Ovarian 35-70% resistance • Radiosensitivity
• Bladder 31-48% • Poor outcome
• Renal cell 50-90%
• H&N 80-100%
• Glioma 40-63%
• Oesophageal 43-89%
Effects of blockade of EGFR-signaling EGFR Status and Local Control in Murine and Human Tumours
Monoclonal antibodies
Small molecule inhibitors

NO DOWNSTREAM SIGNALING
VEGF
angiogenesis
    MMP9
invasion
DNA-repair PI3K-AKT JAK-STAT pathway Pro-proliferative

survival pathway regulating gene RAS-MAPK pathway
transcription
Akimoto et al. Clin. Cancer Res. 1999; 5: 2884-90 Eriksen et al. Int. J. Radiat. Oncol. Biol. Phys. 2004; 58: 561-6

4:00pm
EGFR and L-R Control in CHART Trial
Bentzen et al. JCO 2005; 23: 5560-7
Cetuximab Plus RT
Bonner et al. NEJM 2006; 354: 567 JBC 2005; 280: 31182-9
Influence of Tissue Oxygenation on Tumour Control
100 OER = 8/3.25 = 2.5
02 diffusion
gradient hypoxic
10-1
10-2
Tumour
blood anoxia euoxic
10-3
vessel hypoxia
euoxia
1 2 3 4 5 6 7 8 9 10
RT dose (Gy)
Thomlinson and Gray. Br. J. Cancer 1955

4:00pm
Meta-analysis of hypoxia modification Loco-regional Control According to Type of Modifier
Endpoint Trials Patients RT+sensitiser RT alone (%) OR Modifier Trials Patients RT+sensitiser RT alone (%) OR
(%) (%)
L-R control 65 8652 52 45 1.29

(1.19-1.41) HBO/oxygen 24 2667 59 49 1.47
(1.26-1.71)
Survival 77 10037 35 31 1.19
(1.09-1.29)
HCS 41 5974 48 42 1.24
Distant 21 4138 20 21 0.93 (1.12-1.38)
metastasis (0.80-1.07)
RT 26 3916 18 17 1.09 Transfusion 1 135 84 69 2.27

complications (0.93-1.29) (1.00-5.20)
Overgaard and Horsman. Semin. Radiat. Oncol. 1996; 6: 10-21
L-R Control According to Tumour Site
Endpoint Trials Patients RT+sensitiser RT alone OR

(%) (%)
Head and 27 4250 46 39 1.35
neck (1.20-1.53)
Cervix 16 2877 65 58 1.31
(1.13-1.52)
Bladder 12 707 50 45 1.24
(0.93-1.67)
Lung 8 624 37 33 1.19
(0.85-1.65)

4:00pm
L-RC DSS
1. No transfusion 1. No transfusion
2. Transfusion 2. Transfusion
Hardee et al. PLoS One 2007; 6: e549 Int. J. Radiat. Oncol. Biol. Phys. 2009;73:391-8.
VEGFs and VEGF-Rs Normalisation of Tumour Vasculature as an Adjunct to RT
VEGF-gene family: VEGF-A,B,C,D,F
VEGF-A: blood vessel

VEGF-C,D: lymphangiogenesis
VEGF-A: 4 isoforms VEGF121,165,145,183
VEGF-R1 (Flt-1): (angiogenesis, metastasis)
VEGF-R2 (KDR): (tumour angiogenesis)
VEGF-R3 (Flt-4): (lymphangiogenesis)
DNA Repair – Classical Descriptors Targeting DNA Repair
• Sublethal damage repair (Elkind recovery)

– demonstrated in split-dose experiments
– significant recovery in first hour, complete by 4 hours
• Potentially lethal damage repair

– demonstrated in delayed plating experiments
– recovery during replicative quiescence
– time course similar to SLD repair
Khanna and Jackson 2001

4:00pm
Homologous recombination - HR Non-Homologous End Joining - NHEJ
Carried out primarily by 7 proteins
HR versus NHEJ ATM Inhibition as a Radiosensitiser
• NHEJ • HR
– Repairs most DSB - 80% – Repairs fewer DSB – 20%
– Important for – Important for
radiosensitivity radiosensitivity Vehicle, KU58050
– Error prone – Error free

– All parts of the cell cycle – S and G2 phase
– ½ time ~2-4 hours – responsible for change in
KU55933
– Defects rare in cancer sensitivity in the cell cycle
– Proliferating and non- – ½ time long – 24hours?
proliferating tissues – Varies more between cell
lines (high in stem cells)
– Defects common in cancer
Hickson et al 2004
– Proliferating tissues
PARPi as a Potential Radiosensitiser Strategy (1) PARPi as a Potential Radiosensitiser Strategy (2)

4:00pm
PARPi as a Potential Radiosensitiser Strategy (3) Favourable Tumour for RT Cure
Probability of normal tissue damage (%)

Probability of tumour control (%)
40%
Complication-free
cure = 35%
5%
70 Gy
Radiation dose
Tumour dose-response curve
Normal tissue dose-response curve

Harrington and Nutting, Curr Opin Investig Drugs 2002
Unfavourable Tumour for RT Cure Genetic fingerprinting to predict response?

• New techniques permit analysis of tumour
– DNA profile (genome)
Probability of normal tissue damage
– RNA profile (transcriptome)

Probability of tumour control
– Protein profile (proteome)

– Kinase profile (kinome)
30% • Bioinformatics allow simultaneous analysis of the interplay of

100s or 1000s of genes
20%
Complication-free
cure • New prognostic information
5% – Recurrence
– Dissemination
70 Gy – Response to therapy
Radiation dose (Gy)
Expression and Tissue Microarray

4:00pm
Conclusions
• The 6 hallmarks of cancer provide a mechanistic (rather than

descriptive) framework for considering radiobiology
• Tumour repopulation has been validated as a target for molecular
therapies
• Tumour oxygenation remains a difficult therapeutic target
• DNA repair processes represent very promising potential therapeutic
targets
• Genetic analysis of the difference between sensitive and resistant
tumours is providing insights for the development of new treatments

9:00am
Introduction I
Target volume definition in Head and neck cancer is a highly attractive IMRT site:
• Easily immobilised with limited organ motion
head and neck cancer • Steep dose response curve for SCC supports dose
escalation strategies
Dr Christopher Nutting
Royal Marsden Hospital and • Complex target volumes and multiple OAR close to
Institute of Cancer Research targets:
– OAR with in parallel FSU - 3DCRT does not work!
– OAR with in-series FSU allows clinical gains from partial
tissue sparing
Introduction II
Two components:
Accurate target volume definition is a potential pitfall
of head and neck IMRT and is required for:
• Adequate clinical results
1. NODAL OUTLINING
• Education and training – Consistency
• Clinical trials - Comparison of outcomes 2. PRIMARY TUMOUR OUTLINING
e.g.PARSPORT Trial
NODAL
Two components: OUTLINING
Patterns of spread documented in
1. NODAL OUTLINING large retrospective surgical series.
Robbins Lymph Node classification :

– Level Ia: submental triangle
2. PRIMARY TUMOUR OUTLINING – Level Ib: submandibular
triangle
– Level II: upper jugular
– Level III: mid jugular
– Level IV: lower jugular
– Level V: posterior cervical
triangle
– Level VI: anterior neck Sobotta, 1982
Thursday 17th June 2010 1

9:00am
CONSENSUS OUTLINING GUIDELINES

NODAL OUTLINING: Leve Cranial Caudal Anterior Posterior Lateral Medial
l
Problems Ia Mandible Hyoid bone Symphysis

menti
Body hyoid
bone
Ant. Belly of
digastric m.
n.a.
Ib Cranial edge Hyoid bone Symphysis Post. edge Mandible, Lat. edge of
SCM menti; SCM platysma, ant. belly DG
• Surgically defined boundaries sometimes platysma skin
difficult to identify on CT/MR II Caudal edge

lat. process
Caudal edge
hyoid bone
SM,ICA,post
belly DG
Post
SCM
edge Medial edge
SCM
Med.
ICA,PS
edge
C1
• Neck position is different in radiotherapy III Caudal edge Caudal edge Ant edge Post edge of Medial edge Med edge
patients / compared to surgical series hyoid bone cricoid cart. SCM, postlat
edge SH
SCM SCM ICA,PSm
• Consensus outlining guidelines endorsed by IV Caudal edge

cricoid cart
2cm cranial
to SCJ
Ant
SCM
edge Post edge of
SCM
Medial edge
of SCM
Med
ICA, PS
edge
EORTC and RTOG…… V Cranial edge

hyoid bone
Cervical
transverse
Post
SCM
edge Ant edge
trapezius m
Platysma,
skin
PSm
• Contrast Enhanced CT scan essential VI Caudal edge

vessels
Sternal Platysma, Between Thyroid gl., n. a.

thyroid manubrium skin trachea and skin, SCM
cartilage oesophagus
Gregoire et al 2002
RP nodes: Base of skull to cranial edge body hyoid bone

Fascia under pharyngeal mucosa
RETROPHARYNGEAL
NODES
medial edge ICA
medial edge ICA

Base of skull
to
C3
Midline structure
Sobotta, 1982 Prevertebral fascia
Level Ia: Mandible to hyoid bone

Level Ia- Symphysis menti/ platysma
SUBMENTAL
TRIANGLE
Anterior belly of digastric muscle
Anterior belly of digastric muscle
Anterior belly of
both digastric
muscles and hyoid
bone
Midline structure
Sobotta, 1982
Body of the hyoid

9:00am
Level Ib: Cranial edge submandibular (SM) gland to hyoid bone

Level Ib-
Symphysis menti/ platysma
SUBMMANDIBULAR Anterior and posterior belly of the
TRIANGLE digastric muscle and body of the
Lateral edge anterior belly of digastric muscle

Lateral edge anterior belly of digastric muscle
mandible
Mandible/platysma
Mandible/platysma
Sobotta, 1982
Posterior edge SM gland
Level II: Caudal edge lateral process C1 to caudal edge hyoid bone
Level II – UPPER Level IIa: post border- ant edge SCM
DEEP CERVICAL SM gland, ICA, post belly Digastric
NODES
Anatomy:

medial edge SCM
medial edge SCM

(hyoid) to skull base.
the lateral border of the
stylohyoid muscle
– LEVEL IIa: anterior to the

spinal accessory nerve
– LEVEL IIb: posterior to the
spinal accessory nerve
Sobotta, 1982
post edge SCM
Level III: Caudal edge hyoid bone -- caudal edge cricoid cartilage
Level III – MIDDLE
JUGULAR NODES Ant edge SCM , posterolateral edge Sternohyoid
Anatomy:
medial edge SCM

medial edge SCM

(hyoid) to the junction of the
IJV(cricoid level).

the sternohyoid muscle
Sobotta, 1982 post edge SCM

9:00am
Level IV: Caudal edge cricoid cartilage -- 2cm cranial to SCJ

Level IV– LOWER
JUGULAR NODES
Ant edge SCM m
Anatomy:
medial edge SCM
medial edge SCM

• From the junction of the
IJV(cricoid level) to the
clavicle.
• Posterior border of the SCM

to the lateral border of the
sternohyoid muscle
Sobotta, 1982 post edge SCM
Level V– POSTERIOR Level V: Cranial edge hyoid bone to Transverse cervical vessels
TRIANGLE NODES Post edge SCM
Boundaries:
• Anterior border of the
trapezius muscle to
PSm
Platysma
PSm
Platysma
Posterior border of SCM
• Skull base to Clavicle
It includes the
supraclavicular nodes
Sobotta, 1982
Anterior edge trapezius m.
Level V: Cranial edge hyoid bone to Transverse cervical vessels Level V: Cranial edge hyoid bone to Transverse cervical vessels
Post edge SCM Post edge SCM

Platysma
Platysma
PSm
PSm
PSm
Platysma
anterior edge trapezius m. anterior edge trapezius muscle

9:00am
Level V: Supraclavicular nodes

Lymph node levels I-V and RPN’s bilaterally
Lymph node levels Ib-V bilaterally Problems with guidelines

• Post operative neck – where anatomy is
rearranged compared to un-operated neck
• Node positive neck – again anatomy is
II distorted, and spread outside nodes (ECS)
II
Ib Ib commonly occurs
III
III
V • Controversy over which nodal groups are to
V IV IV be included in target volume for each
tumour site
Nutting et al 2003
PRIMARY TUMOUR OUTLINING

Two components:
• NO ACCEPTED GUIDELINES
1. NODAL OUTLINING • Sources of information:
– Tumour site/ stage
– Tumour natural history
2. PRIMARY TUMOUR OUTLINING
– Anatomical descriptions
– Surgical experience
– Lessons from conventional radiotherapy

9:00am
PRIMARY TUMOUR Clinical example:

OUTLINING T4N2bM0Hypopharynx
• GTV: Gross Tumour Volume (CT/MRI,
EUA, clinical examination, PETCT)
• CTV (customised) = GTV+1-2cm margin
• Edited out of air, skin, bone (if no risk
of involvement)
• Edited to encompass entire organ when
indicated
• PTV= CTV+ 3mm margin Tumour GTV I
T4N2bM0Hypopharynx T4N2bM0Hypopharynx
Tumour and node GTV I and II and CTV I and II

Tumour and node GTV I and II (whole organ, and node with margin)
T4N2bM0Hypopharynx T4N2bM0 Hypopharynx
High dose CTV (composite of CTV I and II)

Add elective CTVs

9:00am
T4N2bM0 Hypopharynx OUTLINING OF OARs
• SPINAL CORD
• BRAIN STEM
• OPTIC NERVE
• LENS
• RETINA
• OESOPHAGUS
• ORAL CAVITY, LARYNX, TRACHEA
3D reconstruction High dose and elective CTVs
CTV + 3mm= PTV
EDITING:
– PTV edited out of SKIN to avoid necrosis
Preliminary Clinical Results
– Lower dose volumes out of high dose volumes
Patterns of recurrence SCC H&N Conclusions I

• Dawson et al, 2000.
PS- IMRT Median FU 27 months (6-60) 58 patients • Target volume definition is critical
In high dose volume 10 component of conformal radiotherapy
Marginal 2 (ipsilateral electively treated neck)
• It represents the largest uncertainty in head
No recurrences in region of parotid gland and neck treatment planning
• Chao et al, 2003
• International guidelines should be used to
PS- IMRT Median FU 26 months (12-55) 165 patients define elective lymph node targets
In field/marginal 12
Outside 6 (5 lower,1 post neck)
No recurrences in contra-lateral high level 2 nodes (partially spared)

9:00am
Conclusions II
• Primary target volume definition is
controversial and a consistent approach is
recommended
• New imaging modalities are yet to be
integrated into these systems
• All patients treated using these guidelines
should be carefully followed up to monitor
outcome as part of clinical trial protocols

9:45am
FDG-PET in head and neck Head and Neck cancer

cancer 555,000 new cases world wide
Romania 2010 300,000 deaths per year
Low and medium income countries
90% SCC
Tobacco, Alcohol in 75%
Genetic factors
Sheila Rankin
Guy’s & St.Thomas Human papilloma virus (HPV)
London
FDG-PET in Oncology
FDG-PET in Head & neck cancer
Advantages of functional imaging
Indications • Identifies metabolically active tissue
• Primary extent of tumour • Depend on activity not size
• Nodal staging. • Assess response prior to size change
• Metastases • Quantitative measurements - SUV
• Treatment planning
• Whole body imaging technique
• Response to treatment – post CRT
• Post treatment anatomic distortion less
• Recurrence
significant
• Unknown primary
Combined PET-CT systems

CT PET
Physiologic uptake
Muscles
Mucosa
Advantages
Lymphoid tissues
•Accurate co-registration
Tonsils
•Decrease overall acquisition time
Salivary tissue
Disadvantages Benign uptake in thyroid adenomas/
• radiation – dose by 1/3 (8mSv) thyroiditis
• contrast/breathing artefacts

9:45am
Waldemyers ring, oral floor, larynx, thyroid

assessed
590 patients. No history head & neck cancer
Elevated uptake in 60%
Asymmetric elevated uptake with no CT correlate on
CE CT in 49%
Follow up > 1 year
Only 2 developed cancer on follow up
Asymmetric uptake does not predict development of
cancer
Huesner TA. E J Nuc Med Mol 2009

Huesner TA. E J Nuc Med Mol 2009

9:45am
PET/CT compared to PET alone

68 patients. 157 foci
• 74% better localised in treated areas
• 58% better localised in untreated
areas
• Decrease number of equivocal
lesions
• Increase accuracy 90% to 96%
• Altered management in 18% CT from CT
• 11% equivocal PET/CT
Schoder. Radiology 2004
CE CT or non CE CT in CE CT or non CE CT in PET/CT

FDG/PET T T accuracy N detection/
40 patients head & neck cancer detection accuracy
CE 98% 75% 92% /90%
PET/CT
Non CE 95% 73% 92%/ 90%
PET/CT
Diagnostic 87% 53% 83%/ 79%
CT
Diagnostic 95% 58% 88%/ 90%
MRI Yoshida K, E J Nuc Med Mol 2009
Yoshida K, E J Nuc Med Mol 2009
CE CT or non CE CT in PET/CT
CE CT WB CE HN FDG-PET in Head & neck cancer
PET/CT PET/CT
Nodal sensitivity 57% 70% 91% Indications
Nodal accuracy 81% 79% 76%
• Primary extent of tumour
• Nodal staging.
• Metastases
• Recurrence
CE HN PET/CT better for small <15mm nodes
• Unknown primary
Rodrigues, J Nuc Med Mol 2009

9:45am
Pre-operative FDG-PET
No information on
Patterns of local
spread
Deep infiltration
Bone and cartilage
destruction
Extent of tumour
Perineural spread
Keyes. AJR.1997.169:1663 Better information
with PET/CT
FDG –PET for synchronous tumours

Pan-endoscopy routinely performed
Second primary in 4.5%
Indications
• Sensitivity 74%
• Specificity 99.7%
• Nodal staging.
FDG PET-CT in 6.1%
• Metastases
• Sensitivity 100%
• Specificity 95.7%
Because of cost only use PET-CT in advanced
disease for distant disease • Recurrence
Hearle Head Neck 2010 • Unknown primary
MRI Versus CT for Nodes

CT
Sensitivity 88-90%,
specificity 39%
PPV 50%, NPV 84%
MRI
Sensitivity 81-82%,
specificity 48%
PPV 52%, NPV 79%
Curtin.
Radiology.1998

9:45am
FDG-PET in head & neck cancer FDG-PET in Staging

54 patients.SCC oral cavity/oro-pharynx. 22 patients
Assessed for nodal disease Nodes Sens Spec Acc
PET CT US/FNA CT 73% 57% 68%
Sensitivity 96% 85% 64% PET 93% 100% 95%
Specificity 90% 86% 100%
Tumour
In 9 (17%), second primary identified on
PET
CT 71%
Stokkel. Annals of Surg.2000;231:229 PET 81% and occult tumour
Bruschini Acta Oto Ital 2003
Added value of PET/CT in retro-

pharyngeal nodal detection
PET/CT
CT/MRI + PET/CT
Improves detection
Sensitivity 62.5% 88.9%
Specificity 60.0% 85.7% Limitations
Accuracy 60.6% 86.7% Small numbers
PPV 33.3% 72.7%
NPV 83.3% 94.7% Chu Head & Neck Surg
False + ve 10 3 2009
False - ve 3 1
Chu Head & Neck Surg 2009 TP FP
FDG-PET in Head & neck cancer Screening for metastases

2-18% at presentation
Indications
Not screen all patient
• Nodal staging.
Risk high if N2 or N3
• Metastases PET- CT more sensitive than PET or CT
• Treatment planning (63% vs 53% vs 37%)
• Response to treatment – post CRT PET-CT cost effective
• Recurrence Uyl de Groot J Nuc Med 2010
• Unknown primary

9:45am
SCC in neck nodes

Screening for distant tumours
SCC head and neck
• High association with 2nd primary
• Metachronous lesions - 22 % within 5
years
• Synchronous tumours 8%
• Laryngeal cancer - 26% risk of
developing lung cancer in next 14 years
Pyriform fossa cancer

FDG-PET in staging
56 patients head and neck cancer
Primary- sens 93%, spec 100%, acc 94%
Nodes - sens 94%, spec 97%, acc 96%
Mets - sens 83%, spec 100%, acc 98%
Additional information in 22%

Altered management in 11%
Sigg J.oral maxfac Surg 2003
PET in Radiotherapy planning

FDG-PET in Head & neck cancer Advantages
• Reduce intra-observer variability of GTV
Indications • Reduce size of GTV
• Primary extent of tumour • Identify tumour missed by CT/MR
• Nodal staging. • Identify areas requiring boost
• Metastases Disadvantages
• Treatment planning • Poor spatial resolution
• Response to treatment – post CRT • False positives due inflammation
• Recurrence • Lack of standard segmentation method
• Unknown primary • 5% change in threshold contour may
increase volume by 200%

9:45am
18F FLT (fluorothymidine)

Head & Neck cancers show avid uptake
Red = GTV on CT
Green = PET visual
False positives in nodes
Orange = SUV 2.5 Accurately images tumour during RT
T4N2
Yellow = 40% max FDG influenced by inflammatory response
intensity FLT pre RT
Dk blue = 50% max Red=GTVct
intensity
Lt blue = adaptive
threshold base on
FLT post
signal:background
ratio RT 8x2Gy
T4N2
Troost J Nuc Med 2010 Troost J Nuc Med 2010
Tumour delineation in HNSCC PET- CT in treatment planning

CT and MRI T2W and T1W + gd - similar volumes
GTV FDG < GTVCT Metabolic treatment volume of 40ml
All local recurrences in GTV FDG predict response
Boost dose to GTV FDG within GTVCT > 40ml - lower rate complete response
FMISO - amount and level of hypoxia negative > 40 ml – worse disease free survival
correlation with DFS. Recurrence outside SUV no correlation with outcome
baseline hypoxic area
? boost dose to permanent areas of hypoxia Chung Clin Cancer Research 2009
Definition of metabolic volume

FDG
Dirix J Nuc Med 2009
difficult especially nodes
FMISO post RT Schinagl Radiother Oncol 2009
FDG-PET in Head & neck cancer Management following CRT

Adjuvant ND after CRT is standard of
Indications care
Decrease risk of nodal recurrence
• Nodal staging.
• Metastases
Prognostic information
• Treatment planning Increased pain
• Response to treatment – post CRT Functional disability
• Recurrence Cost
• Unknown primary

9:45am
Cost effectiveness of PET/CT in Monitoring response following

deciding need for ND chemoradiotherapy
FDG PET at least 8/52 after treatment
Compared 3 strategies using Markov model
NPV = 95%
• Dissect all patients
PPV = 71%
• Dissect patients with residual disease on CT Porceddu Head & Neck 2005
• Dissect patients with RD on PET-CT NPV 100%

Probabilistic sensitivity analysis performed PPV 40%
ND based on RD on PET-CT dominant strategy Planned neck dissection can be deferred
PET-CT cost effective $500,000/QALY If CR of primary and negative but palpable
nodes close follow up with PET-CT can be
Sher Annals Oncol 2009 used Rabalais. Laryngoscope 2009
FDG-PET after DXT Role of PET-CT in neck dissection

Clinically No after CRT
12 patients. 1 month after DXT
For planned ND following CRT
Sens Spec PPV NPV Scan between 8-11 weeks
CT/MR 90% 100% 100% 50% Sensitivity 60%, specificity 36%
PET 45% 100% 100% 14% • FP – inflammation FN – necrosis
Rogers. Int J Rad oncol 2004 NPV 67% PPV 30%
3-6 months after DXT Regional recurrence post ND 6% - similar rate
to observation
PET 100% 81% 46% 100% Cannot use early PET/CT to predict need for
Conessa Ann Otol Rhin 2004 ND Gourin Laryngoscope 2009
Monitoring response following CRT Prognostic information and PET

Low tumour SUV post chemoRT Retrospective study of PET performed after RT
or complete response on CT Nodes - NPV 99%, PPV 71%
correlates with improved survival (tumour Tumour – NPV 98.7%, PPV 32.4% - especially
NOT nodes) larynx. High uptake poor quality of life
CT and PET stratify patients into risk groups PET positive
• worse 3 year overall survival (57% vs 73.6%)
• worse disease free survival (42.5% vs 70.5%)
Scan after 12 weeks
Yao. Int J Radiol onc biol phys 2009
Moeller Int J Rad Onc Biol 2010

9:45am
FDG-PET in Head & neck cancer Recurrent

Indications cancer of
tongue
• Nodal staging.
• Metastases
• Recurrence
• Unknown primary
Previous Ca Tongue. New palpable

nodes ? recurrence
2009
2009
2010

Indications
• Nodal staging.
• Metastases
• Recurrence
• Unknown primary

9:45am
Unknown primary
2.3 - 4.2% of all cancers
Site identified in only 20% ante mortem
Commonest site – lung, pancreas, oropharynx
Meta analysis PET/CT tumour detection in
37%
False positives
• Lung
• Oropharynx
False negatives Kwee TC Eur Radiol 2009
• breast
Blind biopsy 10%

CT/MR guided FDG-PET in unknown primary
biopsy 20%
PET guided 40% Blind biopsy 10%
in one series CT/MR guided biopsy 20%
10% of +ve PET PET guided 40% in one series
was –ve on biopsy 10% of +ve PET was –ve on biopsy
Keyes.AJR.1997.
Keyes.AJR.1997.
Sens 62%, spec 16 patients CT/MR negative

66%, PPV 62%, PET TP in 8, FN in 2, 6 no tumour on F/U
NPV 62%
Sens 62%, spec 66%, PPV 62%, NPV 62%
Management Management altered in 50%
altered in 50% Wong Clin Onc 2003
Wong Clin Onc 2003
PET/CT in Head and Neck

Cancer
Conclusions
FDG- PET used for:
• Nodes
• Metastases
• Recurrence/Response
• Unknown primary
New PET tracers

11:30am
Inverse planning for intensity

modulated radiation therapy
Romania June 2010 Inverse planning for IMRT
Steve Webb
Head
Joint Department of Physics
Institute of Cancer Research (University of London)
and
Royal Marsden NHS Trust
The key historical stages leading to inverse

planning were:
(i) <1920s:
<1920s: no planning,
(ii) 1920s-
1920s-1960s “hand planning”
planning” (overlay of
isodose curves on transparencies),
(iii) 1960s computer planning (firstly in 2D,
Summary of key points on then in 3D). This was “forward planning”
planning”,
inverse planning (iv) 1982 first analytic inverse-
inverse-planned
problem,
(v) 1988 Censor and Brahme’
Brahme’s analytic
inversion techniques,
(vii) 1988-
1988-2010 explosion of techniques for
inverse planning,
(viii) 1992 first commercial inverse-
inverse-planning
system, (ix) 2010 most companies offer (in one
form or another) “inverse planning”
planning” .
“Forward planning”
planning” means “informed trial,
error and re-
re-trial”
trial”. Beam type, energy, number
The Royal Marsden Hospital developed are chosen and the planner adjusts
orientations and beamweights until an
one of the first-
first-ever computer treatment
acceptable plan is found.
planning systems – the RAD8 in 1972.
Thousands of machines were sold. This Combined with field-
field-shaping (via MLC or
enabled physicists to do (2D) “forward blocks) this is still the workhorse technique
planning”
planning” in realistic time. today for many clinical situations. It works at
the level of assuming patient geometries are
generically similar.

11:30am
1. Inverse planning can be applied to (non IMRT)

“Inverse planning”
planning” (as its name geometrically conformal CFRT. “Inverse planning”
planning”
does not mean “planning IMRT”
IMRT”.
suggests) is the reverse process. The
planner specifies the required 3D dose 2. “Inverse planning”
planning” is largely synonymous with
distribution including PTV and OAR “plan constrained optimisation”
optimisation”.
requirements and constraints. 3. Most physicists believe inverse planning is
absolutely necessary for IMRT. Some disagree and
A computer algorithm then finds a direct forward techniques are published.
beam-
beam-configuration solution best 4. Inverse planning is characterised by some well-
well-
matched to the prescription. defined cost function. Physicists may argue over the
choice but once specified it is this which drives the
optimisation and the photon-
photon-tissue interactions which
Note:
determine the outcome.
8. If the goal of optimised inverse planning

5. The principles of all inverse planning are was ever to “replace the human planner”
planner”
the same; the differences lie in the detail. nothing could now be further from the truth.
Inverse planning has opened up more choices
6. Inverse planning does not deliver “the but provided sophisticated tools to navigate
optimum plan”
plan” because some parameters (e.g. the choices.
numbers of beams, beam energy) are fixed
ahead of the optimisation. It delivers the 9. Inverse planning is only part of the
“constrained optimum plan”
plan”. “radiotherapy physics chain”
chain”. Given
“garbage-
garbage-in garbage-
garbage-out”
out” concept, the clinical
7. From about 1988 to 1998 most inverse plan outcome depends, not only on the planning,
algorithms (PEACOCKPLAN/CORVUS but on the determination and specification of
excepted) were one-
one-off local developments in PTV, OARs,
OARs, dose calculation algorithm, dose
a research setting. From 1998 this dramatically delivery technique, verification of accuracy,
changed and most planning system companies biological estimation of outcome etc.
offer inverse planning.
What is treatment plan optimisation?

Aim of conformal radiotherapy – P.T.V. & O.A.R.
Forward treatment planning – tradition – human
optimisation.
Desirable treatment options for increased precision with
automation:
(1) use of larger number of fields
(2) use of non-coplanar fields
(3) use of B.E V-shaped M.L.C. fields Symbolising the

essence of IMRT
(4) I.M.B.s.

11:30am
For these, forward treatment planning (T.P.) is

impossible because:
(1) too many possibilities to explore: too little human

time
(2) little chance of arriving at optimum T.P. by trial-and-
error
(3) if acceptable T.P. found, no guarantee it is the best
(4) no criterion to express precision
 Must use Inverse Treatment Planning to solve:
“Given a prescription of desired outcomes, compute
the best beam arrangement”.
Solve by computer with human guidance, not by

human alone.
Classes of inverse T.P. techniques Simulated annealing: general concepts
Iterative optimisation technique to find global minimum

2 broad classes: of a cost function in the presence of potential multiple
local minima.
(1) Analytic techniques – inverse computed Used in a variety of fields

tomography
First used in medical imaging by Barrett (~1983) to minimise a quadratic
(2) Iterative techniques – including simulated cost function
annealing
First used for SPECT by Webb (~1987)
Introduced to radiotherapy treatment planning by Webb (~1988)

Some optimisation tools combine both
Further developed by Mohan (New York).
Analogy
dose beams
S.P.E.C.T.
γ camera
Beam sinogram
All 2D images

11:30am
Application to radiotherapy treatment planning

Cost = (rImportance (r) [Dp(r) – Dn (r)]2)½
Computation of I.M.B. profiles
where Dp (r) is dose prescription

Medical imaging analogy
Consider (for convenience) a quadratic cost function
and Dn (r) is dose at nth iteration
 
V n
  ( D p r   Dn r  2  1
2
 r 
Simulated annealing
Digital dose prescription Dose with optimised beams Grain of beam
element weight
Aim : minimum V
Acceptability of positive-
positive-potential changes
skier
Probability of acceptance = exp(-
exp(-ΔV/kT) If ΔV < 0 accept grain
ΔV = potential change due to grain placement If ΔV > 0 accept grain with probability exp (-
(- ΔV/kT
V/kT))
K = Boltzmann’
Boltzmann’s constant (T is temperature and k is Boltzmann’
Boltzmann’s constant
T = temperature
-ve ΔV
exp(-
exp(-ΔV/kT
V/kT))
+ve ΔV
Trap
Amorphous
state
(local
minimum)
Decreasing potential energy
trap
Temperature T high T -ve ΔV
Strategy: start at high temperature and then cool such that T is reduced
Global minimum
slower than 1/ ln (n) Crystal analogy (crystalline state)
This guarantees convergence to a global minimum

11:30am
Dose is surrogate for biological outcome

Arguments for biological cost functions
TCPn = f1  Dn (r)  r part of P.T.V.
NTCPn = f2  Dn (r)  r part of O.A.R.  The aim of radiotherapy!
So: Argument against

1. Maximise TCP subject to maximum NTCP.
2. Minimise NTCP subject to minimum TCP.
3. Maximise TCP x (1-NTCP).  Models relatively new (and only models, not “real”
4. Combine dose and biological cost in some way? physical quantity)
Note a physical parameter cannot be a goal for optimisation  Data are based on limited observations
and a constraint at the same time.
An “across the pond” diversity U.K. vs U.S. approach
Practicalities Results (3D dose distributions) evaluated by

same tools as results from forward planning:
S.A. substitutes only for one part of the
planning process.
i.e. D.V.H.
isodoses
Still needs to be fed:
3D shaded surface dose distributions
dose ribbons
1. P.T.V., O.A.R. from 3D C.T., M.R, P.E.T.,
S.P.E.C.T. a posteriori T.C.P., N.T.C.P. etc.
2. Dose to each dose-space voxel per unit
beamweight  S.A. should be part of an integrated 3D T.P.
3. Biological model and data system
4. Prescription and constraints on plan and
beamweights
Required features of S.A.

Downsides
Simulated annealing’s flexibility is also its weakness
1. + and – grains : mechanism to “undo” structure
It needs tuning
2. grain size reduction
Careful choice of grain sizes, number of iterations,
3. beamweights constrained positive (c.f. analytic Type of C.F.
inversion!)
Cooling schemes
4. care to computer aspects of C.F. calculation – at
heart of optimisation
III conditioned problems have C.F.s with a broad
region of shallow curvature in vicinity of minimum =
5. other beamweight constraints many different solutions (beamweight configurations)
for same cost.

11:30am
The ideal system would provide:

The ideal scenario which no planning system
currently offers
 Forward and inverse planning together.
 Most treatment planning algorithms were  Planning for MLC-shaped fields and for 2D IMBs.
developed as standalone facilities to do  Planning for protons and heavy particles.
specific tasks.  Ability to switch in different cost functions and indeed
 Commercial systems generally implement
different algorithms for inverse planning.
the subset of planning codes for situations
 Compatability with all manufacturers’ 3D imaging
that interest them.
formats.
 No system has everything so comparisons
 Variety of exploration tools for 3D dose distributions.
are difficult on the same patient cases with
the same tools.  Computation of biological cost.
The ideal system would provide:
…………
There is no such thing as an optimum plan!

Conclusion
 An algorithm will only generate a plan which is “best” S.A. works
according to the constraints provided.
 It is well known that the inverse treatment planning

Very flexible tool
problem is ill-conditioned. This means many different IMB
sets can give much the same 3D dose distribution. (The Not as slow as it once was
“Sticky marble in a flat-bottomed bowl” story).
 There is actually no need for the optimum plan (if it “A hard car to drive” – tuning all
existed). What is needed is an acceptable plan = a much important
better plan that could be had without IMBs.
Detailed descriptions of
both theoretical and
practical IMRT + huge
lists of primary
references can be found
in these 4 sequential
books
1993 1997
2000
2004

12:00 noon
Introduction
IMRT planning:
strategies for improving poor  Improving the plan
plans, common errors and – Before, during and after optimisation
plan assessment  Plan assessment
– Volumes, beams and dose distributions
Dr Catharine Clark – Fluences and leaf motions
Adapting volumes Adapting volumes
 Addition of margins to volumes Exclusion of Edit

overlapping
build-up area to
 Editing of volumes ensure skin volumes
sparing
– can define constraints separately for
overlap region
 Creation of ‘dummy volumes’
volumes’
Dummy
Expansion of OAR volumes to
to maximise avoid unwanted
sparing hotspots
Adapting volumes Adapting volumes

Expansion of Additional
PTV to improve non critical
coverage ‘dummy’
volume

12:00 noon
Isocentre position
Adapting volumes
 Symmetric in sup / inf
– maximise use of 5mm leaves
 Avoid too much asymetry in X jaws
– Can cause problems for split beams
Difference in rectal sparing with addition of Rectum-PTV
Isocentre position
Partial blocking of fields
Beam configuration Full beams Asym block

Thyroid PTV dose range 4.2 (0.6) 6.2 (1.1)
Node PTV dose range 10.6 (3.4) 11.2 (1.5)
Spinal cord (maximum) 47.3 (1.8) 44.4 (2.3)
Partial blocking of fields Partial blocking of fields
Careful beam angle choice avoids treating through couch bars Jaws positioned off cord to improve cord sparing

12:00 noon
Acceptable Dose Distribution? Acceptable Dose Distribution?
 E.g in overlap region or close  Unhappy with dose to OAR?

proximity of target to OAR
Increase weight / Decrease weight
stricter objective / relax objective
OARs Target OARs Target
Dose Dose
Acceptable Dose Distribution? Working with constraints
 Unhappy with target coverage?
Decrease weight Increase weight /

/ relax objective stricter objective
OARs Target
Dose
Plan Analysis Plan Analysis
 Following a Still important to review the

full 3D dose distribution
calculation for
Dose volume check for hotspots in
histograms uncontoured tissue
– compare to
plan check that reduced PTV
acceptance doses occur in appropriate
criteria
place, i.e. in regions of
overlap with OARs

12:00 noon
Hotspot location Hotspot location and reduction
 Be realistic
– hotspots happen
– small reduction may
help
 Check location
– Inside target volume
– In uncontoured tissue
– In a sensitive region
108.7% 107.1% away from mucosa
Improving the Plan Improving the Plan

 Delineating hotspots  Dose painting
IMRT plan assessment Volumes and dose distribution
 Volumes
 Prescription
 Beams
 Isocentre
 Dose distribution and coverage
 Fluences
 Leaf motions and split fields
 MU and average leaf gap

12:00 noon
Beam orientation Dose distributions
Anterior (0°)
 Check dose
RAO coverage against
LAO
(300°) primary and
(60°)
elective
prescriptions
RPO LPO
(240°) (120°)
Check in all planes

Fluence Assessment
 Matches treated volumes
 Minimal hotspots
 Check sufficient overlap of split
sections
 Check sections 0 and 1 create total
Leaf motions
 Run leaf motions

 Check average leaf gap
– Ideally < 2cm
 Check MU
– High MU can indicate delivery problems
and small leaf gaps
 Look for tongue and groove

12:00 noon
Tongue and groove Improving the plan summary
 Adaptation of volumes including

dummy volumes
 Balancing constraints and priorities
?  Delineating and painting hotspots
Plan assessment summary
 DVH and dose distribution together

 On screen
 Check against planned constraints
 Verification via calculation or
measurement

12:30pm
Why verify?
Verification of Treatment Delivery Detect gross errors
Role of imaging
Eliminate systematic errors
Helen McNair
Reduce random errors
Research Radiographer
Royal Marsden Foundation Trust and

Institute of Cancer Research
Why verify? Why verify?

Detect gross errors Eliminate systematic errors
Incorrect patient, anatomical site or patient orientation Arise from equipment – affect all patients
Incorrect field size, shape or orientation
Arise from set up – affects one patient
Incorrect isocentre position of unacceptable magnitude
Why verify? Process

Reduce random errors
Reference image
Organ motion
Image acquisition
Daily set up variation
Image registration
Decision

12:30pm
Quality of Reference Image

Process
Reference image
Image acquisition
Image registration
Decision
2.5mm slice thickness
Quality of Reference Image Quality of Reference Image
Small slice thickness for good resolution
Increased time on treatment unit on day 1
Mark reference at CT and isocentre on set
2.5mm DRR 1.25mm DRR
Process Before image acquisition
Reference image
Image acquisition
Image registration
Decision

12:30pm
Image acquisition Image acquisition
Check films
Snap shot
Manual registration
Electronic Portal Imaging
Single exposure
Double exposure or Open field
enhanced
Length of scan; Field of View

Interruptions
Off set isocentres

12:30pm
Image Quality Process
Low dose scan – 2mGy Reference image
Image acquisition
Image registration
Decision
High dose scan – 3.9mGy
Anatomy for template Anatomy for template
Nasal Sinuses Pituitary

septum
fossa
Base of
Stable skull
radiopaque
structures
Vertebral
Clavicles
bodies
Vertebral (anterior
bodies borders)
Image registration Image registration
Region of interest
Manual

12:30pm
Automatic -incorrect Automatic - Correct
Check match- Colour wash Check match - Cut view
Check match –Soft tissue changes Check match –Soft tissue changes

12:30pm
Check match –Tumour changes Check match –Tumour changes
Off line protocols

Process
SAL- Shrinking Action Level
Correct for error

Reference image
Check within Check within Check within Check within Check within
tolerance tolerance tolerance tolerance tolerance
Image acquisition
Image registration
Decision - protocols
Tuesday
Tuesday
Wednesday
Wednesday
Tuesday
Wednesday
Thursday
Thursday
Thursday
Monday
Monday
Tuesday
Monday
Tuesday
Wednesday
Wednesday
Friday
Friday
Tuesday
Wednesday
Friday
Monday
Thursday
Thursday
Thursday
Monday
Monday
Friday
Friday
Friday
Off line protocols Off line protocols

NAL- No Action Level
Correct for
systematic error Less time treatment time involved
Check within Check within Check within Check within Check within
tolerance tolerance tolerance tolerance tolerance More time for image registration
Reduces systematic error which have a greater impact

on treatment margins than random errors
Tuesday
Tuesday
Wednesday
Wednesday
Tuesday
Wednesday
Thursday
Thursday
Thursday
Monday
Monday
Tuesday
Monday
Tuesday
Wednesday
Wednesday
Friday
Friday
Tuesday
Wednesday
Friday
Monday
Thursday
Thursday
Thursday
Monday
Monday
Friday
Friday
Friday
de Boer H et al . 2001
de Boer JC, Heijmen BJ 2002.

12:30pm
On line protocols On line protocols
Correct for error Time pressure for image registration
Can reduce random as well as systematic errors

Tuesday
Tuesday
Monday
Tuesday
Wednesday
Thursday
Friday
Wednesday
Wednesday
Tuesday
Wednesday
Thursday
Thursday
Thursday
Monday
Monday
Monday
Tuesday
Wednesday
Friday
Friday
Tuesday
Wednesday
Friday
Monday
Thursday
Monday
Thursday
Friday
Friday
Brock K 2002
Van de SJ 1998
On line correction
Back up
Align Start Finish
patient treatment treatment
Image
time
Difference in CBCT and EPI

Mean (SD) p value
Correction Treatment Superior/Inferior 0.7 (2.4) < 0.001
Image time
patient Borst IJROBP 2007
Guidelines Accuracy and reproducibility
Determine random
and systematic errors
Reference image
Image quality
Image registration
Effective protocols
Training and competency assessment

2:00pm
Role of Imaging
 Characterisation of a neck mass
Imaging the Thyroid  Assessment of the patient with abnormal
thyroid function
 Assessment of the multi-
multi-nodular goitre
Dr Julie Olliff  Assessment of the incidental thyroid
University Hospital Birmingham nodule
 Staging of proven malignancy
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP  Diagnosis of recurrent cancer
Characterisation of neck mass Neck mass
Ultrasound  Congenital
 Anatomy  Arrest of descent
 Solid or cystic  Overdescent
 Agenesis/hemiagenesis
Agenesis/hemiagenesis
 Single or multiple
 Incomplete degeneration of thyroglossal duct
 Blood flow
with fistulous tract or thyroglossal cyst
 Assessment of cervical lymph nodes
 FNA/biopsy
Neck mass Non-

Non-toxic goitre
 Autoimmune disease and thyroiditis  ? Airways obstruction

 Graves Disease – often non specific. Thyroid  ? Anatomical delineation
enlarged, hyperechoic,
hyperechoic, without discrete
 Assessment of nodules
nodules, increase in vascularlty.
vascularlty.
 Hashimoto’
Hashimoto’s thyroiditis – size variable.
Diffusely abnormal echotexture.
echotexture. In end stage
may be small and fibrotic.
fibrotic.

2:00pm
Prevalence of thyroid nodules Diagnosis of thyroid nodules
 Prevalence of thyroid nodules - 50% at

postmortem – Mortensen 1955  Cysts
 Prevalence on US 67% - Ezzat 1994  Colloid nodule
 Prevalence of occult cancer 2% - Bisi 1989  Thyroiditis
 Benign follicular neoplasm
 Thyroid carcinoma
Increased risk of malignancy Evaluation of thyroid nodules

 Calcification  No blood flow = no malignancy
 Hypoechogenicity  Perinodular flow = no malignancy (2
 Irregular margins suspicious/65)
 Absence of halo  Risk of malignancy increases as
 Predominantly solid intranodular flow becomes more dominant
 Tall shape AP:T > 1
 intra-
intra-nodule vascularity
 Size not a good predictor Chammas et al Otolaryngol 2005;132:874
Detection of incidentalomas (ITN) Incidental thyroid nodules on FDG

and risk of malignancy PET
 4-8% palpation  Systematic review – Shie et al 2009
 50% autopsy (Mortensen et al 1955)
 50% on US in patients >40years (Mazzaferri
(Mazzaferri etal 1993)  18 articles
 67% on US in 97 pts with no known thyroid disease  55,160 patients
(Ezzat et al 1994)
 63/166 ITN in unselected CT our data  571 (1%) unexpected focal thyroid abnormality
 >11.3 % prevalence of malignant or potentially  322 diagnostic confirmation
malignant lesions among incidental thyroid abnormalities
detected on CT Shetty et al 2006  200 (62.1%) benign
 734 patients CT-
CT- 123 pts found to have ITN. 120 had  107 (33.2%) malignant (papillary cancer 82.2%)
histology 15 were malignant (12.5%) Yoon et al 2008
 15 (4.7%) no clear diagnosis

2:00pm
Thyroid nodules and US Malignant features on US

Solid, hypoechoic
 494 patients with nodules on US 
 1.Irregular blurred margins
 Nodules 8-
8-15mms had FNA  2. Intranodular vascular pattern
 3.Microcalcification
 FNA success rate (81%)  Independent risk factors for malignancy
 402 patients had sufficient material  Hypoechoic +1, 2, or 3 predicted 87% of malignant
nodules
 107/402 (27%) suspicious  Using 1cm as cut-
cut-off for FNA 12/31 (39%) cancers
would be missed
 Histology after surgery 31/107 =malignant  Size not accurate in differentiating benign from
malignant
 31/402 (7.7%)
Papini et al 2002 Papini et al 2002
US risk features US FNA

 Overall incidence of thyroid cancer in nodules
 450 consecutive patients undergoing FNA of selected for FNA 9.2-
9.2-13%
incidentally discovered nodules  Number of nodules present does not alter
 94/450 underwent surgery overall cancer rate per patient but will decrease
 20/94 = cancer likelihood of each nodule as the number of
nodules rise.
 Solid hypoechoic only predictor of malignancy
 Cancer will be in non-
non-dominant nodule in
 FNA success rate >1cm 85%, <1cm 69% approx. one third
 FNA should be performed on all solid hypoechoic  Nodule size is not predictive of malignancy
nodules >/= 1cm
Leenhardt 1999
US FNA consensus statement Consensus statement

Solitary nodule
 Solid-
Solid- high sensitivity but low PPV 15.6-
15.6-  >1cm if microcalcification present
27%
 >1.5cms solid or coarse calcification
 Microcalcification -PPV 41.8-
41.8-94% but low
sensitivity present in 26.1-
26.1-59.1%
 Colour flow may be helpful Nodule >2cm
 1cm selected to decrease numbers and  Mixed solid/cystic
unsure about effect on life expectancy of  Cystic but with a solid mural component
lesions <1cm.
Management of thyroid nodules detected at US:
 Substantial growth
Society of Radiologists in US consensus statement
Frates et al 2005

2:00pm
Consensus statement Where are we now?

Multiple nodules
 Consider FNA of one or more nodules using  Incidentalomas on PET with high SUV
above criteria  “clinicians should be cautious about the management of
small or incidentally diagnosed nodules in primary care.
 FNA is likely unnecessary in diffusely enlarged It may be prudent to refer to secondary care for further
glands with multiple nodules of similar US investigation, such as US guided aspiration”
aspiration” Mehanna et
al 2009 BMJ
appearance without intervening normal  166 scans covering all/part of thyroid, 63 pts had ITN.
parenchyma 3000 over one year from CT. US £90, FNA £270 >1
million. ITN>1cm =25 patients extra per week for
USFNA from CT alone. This does not include costs for
 Presence of abnormal lymph nodes overrides US surgery.
appearance of thyroid nodule  Incidentaloma on CT or US potential for massive spend,
anxiety for low return in terms of QUALY’
QUALY’s
 HELP!
Diagnosis of thyroid cancer Staging thyroid cancer
Ultrasound  US useful for staging small primary

 US alone is not reliable in differentiating benign tumours and lymph nodes
from malignant nodules  MRI, CT or either demonstrate extra-
extra-
 BUT used to guide or in combination with FNAC thyroidal or extra-
extra-capsular extension
is the best available technique
 MRI and CT (PETCT) used to demonstrate
 Unreliable for follicular and Hurthle cell nodules
distant metastases
Thyroid Thyroid
CT and MRI
 stage local disease papillary carcinoma
 extra capsular extension  lymph node involvement common
 assessment of superior mediastinum  50% at diagnosis
 retrosternal extension and nodes
 small, cystic ,haemorrhagic, calcified
(VII)
 involvement of larynx, trachea,  distant metastases
oesophagus, major vessels and skin  4-7% at diagnosis
 lymph node involvement (levels I-
I-VII)  lungs, bone, CNS
 distant metastases

2:00pm
Thyroid Medullary carcinoma

follicular carcinoma  Para follicular or C – cells (neural crest
 lymph node involvement less origin)
common  80-
80-90% express calcitonin (better
 2-10% prognosis)
 distant metastases commoner  Calcification may be seen in primary,
 US-
US- solid isoechoic 52%, and nodes and metastases
hypoechoic 42%  May be thallium or gallium avid
 more frequently invades vessels  MEN ll1 and llb
Recurrent disease PET

 NM used mainly for demonstration of  Tumour dedifferentiation may lead to
residual/recurrent differentiated disease decreased or lost iodine-
iodine-accumulating
after thyroidectomy,
thyroidectomy, including medullary ability
thyroid cancer
 Negative I-
I-131 scan but elevated human
 FDG PET has 82% sensitivity for
demonstrating residual/recurrent disease serum thyroglobulin level
(James 1999)  Hung et al Endocr Res 2003 29:169
May miss miliary pulmonary mets
 CT/MR anatomical localisation 
 Frilling et al Ann Surg 2001;234:804
FDG PET-CT indications (non-SCC H&N)
Medullary thyroid cancer

Differentiated thyroid cancer detection of recurrent disease
detection of recurrent disease in patients with
elevated thyroglobulin levels and a negative
radio-iodine scan
FDG 85 patients
sensitivity 78% specificity 79%
FDG PET superior to other techniques
sensitivity 82-94% useful independent of serum calcitonin
specificity 88-100%
Source: Diehl et al EJNM 2001

2:00pm
Conclusion
 There is increasing evidence that US has
a role to play in the characterisation of
thyroid nodules
 CT and MRI can be used to stage
thyroid cancer
 Nuclear medicine and US can be useful
in the diagnosis of recurrence
 CT, PET/CTand
PET/CTand MRI used in the
anatomical localisation of recurrence
 CT and MRI used prior to surgery for
large multinodular goitre

2:00pm
Romania 2010
Radionuclides and therapeutic
avenues
Monitoring metabolic activity
• Assessing proliferation/cell growth
• Assessing blood flow
• Assessing hypoxia
• Assessing apoptosis/cell death
Monitoring drug delivery
PET in Oncology FDG and beyond Monitoring effects of drug delivery
Dr S C Rankin
The perfect tracer

• Easy to make and cheap Positron Emission Tomography
• High yield
• High specific activity
Two anti-parallel
• Only binding to the abnormality in question - 511kEV photons produced
high specificity to target

• Rapid binding and stable
• Rapid clearance from background Positron combines with
electron and annihilates
Positron
• Early imaging
• No reactions in the patient - no toxicity
• low radiation dose Courtesy of
Dr Michael Hofman
Glucose vs. FDG ( 218 Fluoro deoxy glucose)

Blood Tissue FDG-PET in Oncology
Glycogen
Technique
G - 1 - PO4
• Positron 511 KeV. 2 emitted at 1800
Glucose
HEXOKINASE
G - 6 - PO4 • Transmission scan – attenuation correction.
F - 6 - PO4
G-6-P
SUV data
• Emission scan
CO2 + H2O
• Good contrast resolution
FDG HEXOKINASE
• Spatial resolution 5-7 mm
FDG - 6 - PO4

2:00pm
Normal Uptake FDG

FDG-PET in Oncology Cerebral cortex, caudate nucleus
Technique Cardiac. If fasting - 80% no uptake
• 370 M Bq injected IV
Renal tract
• Limited by dose to bladder wall
• Uptake decreased if glucose elevated Thymus in children
– Insulin – FDG to fat and muscle Bone marrow
• Fast 4 -18 hours GI tract
• SUV=FDGregion/FDGdose Body Wt Breast – lactating
• Tumour SUV 2-20
Thyroid
Combined PET-CT systems

Mimickers of malignancy CT PET
• Inflammation
• Wound healing, infection, abscesses,
oesophagitis, pancreatitis
• Radiotherapy - flare response
• Granulomas
Advantages
• TB, sarcoid, histoplasmosis
•Accurate co-registration
• Miscellaneous
•Decrease overall acquisition time
– Paget’s
Disadvantages
– Graves disease
• radiation – dose by 1/3 (8mSv)
• contrast/breathing artefacts
Imaging in Cancer Diagnosis
Diagnosis
Staging
Response
Recurrence or relapse

2:00pm
HIV patient - space occupying lesions on MRI ? Nature

High grade uptake in brain more likely to be lymphoma Localisation
Patient with PTLD ? Site to biopsy

Nodal disease throughout body
Response assessment of treatment
Left axilla most accessible (also note 8 mm node in pelvis) Aims of response assessment of treatment using
imaging
• To assess reliably and non invasively response to treatment

• During
• Post treatment
• To ensure the treatment aim is achieved – (No over or under

treatment)
• To spare the patients unnecessary side effects
• To assess residual disease before clinical recurrence
Breast cancer response assessment

Response to treatment - Burkitts
Staging scan Scan 5 days later post treatment

2:00pm
GIST pre and post Glivac Treatment monitoring:

Stage IIA HL: pre-treatment
Planned treatment: 4 chemo + RT
Stage IIA HL: after 2 cycles chemo

Stage IIA HL: after 6 cycles chemo
Other Isotopes
Limitations to FDG
Choline
11C choline – phospholipid metabolism
• Not readily available in all hospitals
• Not taken up in all tumours • 20 min half life. Less excretion in urine
• High physiological uptake in some areas 18F Choline – phospholipid metabolism
• Non-specific • 2 hour half life. Excretion in urine

• Timing in relation to chemotherapy?
• Purchasers have limited its use
What other agents are available ?

2:00pm
11C-CHOLINE 18F-FDG
11C Choline
P.V. 66 yo, treated with RT for prostate adk; recent

increase of PSA (10 ng/ml). Courtesy Prof
Fanti. Bologna
C-11 choline RE-STAGING OF PROSTATE CANCER
Courtesy of Prof Fazio

Milan
Staging
67 yo RP 2005 PSA 2 ng/mL
SUSPECT OF RELAPSE C-11 choline
Nodes
Sensitivity 80%
Specificity 96%
Accuracy 96%
de Jong J Nuc Med 2003 Milan
78 yr old
psa 4.6ng/ml
restaging

2:00pm
C-11 choline 18F FLT (fluorothymidine)

• Images DNA synthesis and cellular proliferation
• Intracellular trapping of 18 F-FLT by
phosphorylation by thymidine kinase 1
• Thymidine kinase in DNA synthesis with high
enzyme activity in S phase of cell cycle
Milan • Head & Neck cancers show avid uptake
Milan
• SUV decreases after 10Gy
78 yr old
78 yr old psa 4.6ng/ml
• SUV reflects the other more complex kinetic
local recurrence
psa 4.6ng/ml parameters
restaging Menda J Nuc Med 2009
18F FLT (fluorothymidine) Lung cancer

• Tumour FDG FLT
• Compared to 18F-FDG • Sensitivity 89-100% 72-100%
• Lower tumour uptake • Specificity 86-100% 57-73%
• Higher background in liver and marrow • Nodes - FDG more sensitive than FLT
• Not as sensitive in all organs as FDG so not replace it

• Correlated with cell proliferation
• Can indicate response to chemotherapy
• Survival information
Salskov. Semin Nuc Med 2007
18F FLT (fluorothymidine)

• Head & Neck cancers show avid uptake 11C
• False positives in nodes
Methionine
• Accurately images tumour during RT
• FDG influenced by inflammatory response • Incorporated into amino acids
• Use for diagnosis of CNS tumours
• FLT pre RT
• Use for suspected recurrence CNS tumours
Red=GTVct
FLT post RT
8x2Gy
Troost J Nuc Med 2010

2:00pm
SUSPECT OF RELAPSE
C11 methionine
11C-METH
C11
18F-FDG
FDG
C.R. 44 yo, treated with S + RT for glioblastoma Courtesy Prof Fanti

MR inconclusive
Bologna
(18F)Fluoromisonidazole (FMISO)
Tumour Hypoxia
• Determines • Assesses hypoxia
• Treatment response • 18F-FMISO enters cells by passive
diffusion
• Relapse free survival • Reduced by nitroreductive enzymes and
• Overall prognosis trapped in
• cells with reduced oxygen
• Resistance to radiotherapy
• If oxygen present - parent compound
• Mediated by hypoxia inducible factor - HIF-1 regenerated and metabolites not
• Over expressed in cancer cells accumulated
• Accumulates only in viable not necrotic
• Increase mutation rate cells
• Promote gene expression for VEGF
Lee Semin Nuc Med 2007
Normal distribution
DOPA
• Metabolised by • 18Fluorodihydroxyphenylalinine (18
F-DOPA) – use for neuroendocrine
liver tumours and phaeochromocytomas. Combined as PET/CT increases
sensitivity and specificity
• Excreted via • Most lesions > 2cm detected by CT
kidneys • Sensitivity similar to CT at 100% vs 95%
• Specificity better 89% vs 70%
FMISO FDG
Glioma post surgery
Lee Semin Nuc Med 2007
CT PET F-DOPA PET/CT

2:00pm
68Ga – DOTA-NOC
Staging small NET

of the pancreas:
GaDotanoc shows
the primary NET
and some secondary
peripancreatic
lymph nodes
c/o Dr Paolo Castelluci S.Orsola-

S.Orsola-Malpighi Hospital, Bologna
68Ga-DOTATATE scan 18F-FDG scan
Other Isotopes
• 11 C tyrosine – amino acid metabolism vs FDG in
nodes in oropharyngeal carcinoma
• Both identify primary equally
• Nodal disease
• C tyrosine - sens 33%, spec 100% acc 81%
• FDG - sens 67%, spec 97%, acc 84%
• Uptake in salivary glands obscures nodes so
• 11 C tyrosine not useful for nodal staging
68Ga DOTATATE 18F-FDG scan
Krabbe Head Neck 2010
scan
Bronchial Carcinoid
UCL
FDG
C tyrosine New treatment endpoints to evaluate the
effectiveness of drugs
- FDG as marker of tumour viability

- C11 methionine marker of amino acid
metabolism
- FLT marker of tumour proliferation
- Ga dotatate as marker of somatostatin receptor
expression in tumours
- FMISO marker of hypoxia
From Krabbe Head Neck 2010

2:00pm
PET imaging of cancer related processes

Role of PET- CT
Proliferation Clinical
FLT Diagnosis
Angiogenesis Staging
RGD peptides Recurrence
-18F 64Cu, 125I Response monitoring - PERCIST vs RECIST
VEGF - 64Cu
Apoptosis Developmental
Annexin V – 64Cu, 18F Drug development
Hypoxia labelled drug
Misonidazole - 18F tracer evaluation of drug effect
ATSM - 64Cu Appropriate tracer for biological process

4:00pm
Combatting cancer in the third millennium: the contribution of medical physics

and specially radiotherapy physics
Romania June 2010
Steve Webb
Head: Joint Department of Physics,
Institute of Cancer Research (University of London) and Royal Marsden Hospital,
London, UK
Predicting the future is a popular request but can be risky!
“It is said they only ask you to predict the future if you are seriously old
and/or will not be around to know if you were correct”
Hopefully I will live long enough to see if the following come true and to
contribute to some of it!
“Crystal ball gazing” is a very unscientific process. Scientists are trained
to study and analyse situations, report the findings and stop at that.
“Future gazing” is not predicting short-term developments; it is about
being bold, radical and stating what today is impossible and
unthinkable.
So called “Prophets” can be entertaining but at worst look egocentric and
possibly ridiculous.
2001
Some famous prophesy mistakes!

2005
2007 • “I think there is a world market for maybe five computers.”

- Thomas Watson, chairman of IBM, 1943
• “There is no reason anyone would want a computer in their
home.” - Ken Olson, president, chairman and founder of DEC
2009 1977
• “I have travelled the length and breadth of this country and
talked with the best people, and I can assure you that data
processing is a fad that won't last out the year.”
- The editor in charge of business books for Prentice-Hall, 1957
• “640K ought to be enough for anybody." - Bill Gates in 1981
I seem to have
2006 survived 5 previous So beware of prophets!
requests for future
gazing!

4:00pm
Whence comes important progress?

“Big hit science” versus “incremental development”
• [1] “Big hit science” is the invention or discovery

1st example of “big hit science”
of something so important that the medical world
changes for ever because of it. It is what people The invention of x-ray computed
remember, what reaches the media and what
makes some people famous household names. tomography
This is rare!
• [2] “Incremental development” is how the vast
majority of scientists work. Small parts of a big
This revolutionised cancer diagnosis
problem are dissected out and solved.
• Sometimes [2] leads to [1] and often not in any
planned way!
Hounsfield’s lab CT scanner 1969

A small reminder of how a CT scan is formed by filtered
back-projection
April
1972
press

4:00pm
Prototype EMI
scanner now
displayed at
Science
Museum July
2007 against
background of
the real Apollo
10 capsure
1st CT scanner (now in Science

Museum, London)
1994 1990
This was contoversial! These were the people considered to have

“changed the World”. It included politicians, inventors, scientists,
British stamps are the only ones in the world with no country name as we invented humanists but also dictators and media and singing (“pop”) stars.
them. Note how CT scanning was so important it made this stamp
Aug 28th 1919- Aug 12th 2004
It included Godfrey
Hounsfield

4:00pm
Feb 23rd 1924 – May 7th 1998
But this “discovery” did not

really come from no-where. In
fact it was the result of decades
of “incremental science”
This is just one

example of many
“precursors to CT”
From Frank
patent. This
was “almost
CT” in 1940
For a detailed
history please 2nd example of “big hit science”
see this book
from IOP
Publishing The invention of intensity-modulated
(Bristol (1990) radiation therapy (IMRT)
ISBN 0-85274-
305-X
This revolutionised cancer treatment
by radiotherapy
The whole story from 1921 to the 1970s is in my book

4:00pm
How IMRT works How to make a 2D complex modulation by leaf sweep and
This is actually a movie of a brain treatment but the principle is the same step-and-shoot with a multileaf collimator (MLC)
for prostate or any other organ. You see the 9 modulated beams and
the corresponding conformal dose map built up. Leaves move only one way; radiation off between moves
1982 Brahme et al discussed inverse-planning for IMRT for

a fairly special case of rotational symmetry. 1992
The NOMOS
MIMiC
The only device to deliver clinical

IMRT between March 1994 and 1997
World’s first ever “IMRT

School” held at the Strater
Hotel, Durango, Colorado

4:00pm
In 1993 Thomas
Bortfeld and Art
Boyer made the first 70
The Royal Marsden (Sutton)
IMRT s-&-s delivery 60 PPN total 151 PPN H&N
in Houston using a H&N 76 LUNG PAED
Varian machine and

50
Paed 9
taking about 3 hours 40

Patient numbers
Lung (VMAT) 4
to reset fields by 30
hand. They drew this

graphic 3D display of
20
dose. 10
0
2000 2001 2002 2003 2004 2005 2006 2007 2008
Planning Systems used: 2000 Corvus; 2001 – 2003, Helax;

2004 – 2008, Philips Pinnacle (DMPO), except Lung: AutoBeam + Pinnacle.
History (above) is now repeated as a
CT based treatment planning increased from 400 to 2100 patients per year
QA experiment (left) over this period. Forward planned, segmental IMRT for breast, prostate and
rectum tumour sites in 2008: 150 patients per year.
1993 Bortfeld and Boyer conducted the first multiple-static-
field (MSF) experiments using a multileaf collimator (MLC). Courtesy of Jim Warrington
Fluoroscopy to show moving lung / lung tumour

dkfz, Heidelberg
Same patient
250
200
150
100
50
Note the variability

0
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 of motion. (IMRT
Patient number Prostate 154 Lung Cancer/Pleuramesothelioma 98
Different patient research now
Head and Neck 280 Chordoma/Chondrosarcoma 148
Meningeoma 98
Mamma-Ca 25
Pancreas 91
Oesophagus-Ca 43 (courtesy of focuses on motion
others 334
Helen McNair) compensation –
IGRT)
Synchronised Delivery
But this IMRT “discovery” also
MLC
motion
did not really come from no-
MLC
motion
where. In fact it was the result of
decades of “incremental science”
Here are some “precursors”…….
Dr Dualta McQuaid has shown that synchronised leaf tracking can be

performed on an Elekta linac

4:00pm
Principle of
IMRT in 1940
“IMRT” in 1961
The Royal Free “Tracking

Cobalt Unit””.)
The history of IMRT

and subsequent 3rd example of “big hit science”
developments are in
these 4 books
(but which came from much
“incremental science”)
The invention of emission tomography e.g.
(i) Single photon emission computed
tomography (SPECT)
1993 1997
and
(ii) Positron emission tomography (PET)
2000
2004

4:00pm
I guess
we
wouldn’t
stand for
this way SPECT (almost) in the 1960s and 1970s
of
reporting
today!!
It is of course Looking to the

much easier to future is an
look back and unscientific
see from where process. We are
we have come in the realm of
and to hope,
document the expectation,
big speculation and
achievements promise. Nothing
of the past. It is is for sure. If it
PET in the early 1950s, 1960s and 1970s also a proper were certain
scientific what would
process. Facts happen next we
are known! would not be
Data are to research
hand! scientists!
---------------------
So is all lost?
No! We can have
goals and we can
plan the process
Areas in which to work Unusual avenues*….

• It is claimed high-intensity, pulsed electric currents
• Imaging for functional information; SPECT, PET, applied to cancer cells can significantly enhance their
Magnetic resonance imaging and spectroscopy, Ultrasound uptake of cytotoxic drugs.
and Biomedical optics); • the application of photochemical internalization for
• High-speed digital x-ray and CT imaging; treating cancer (“Shine the light, release the drug”).
• Need to gain a better understanding of tissue motion on • Biomedical optics may aid cancer screening and
many timescales; molecular imaging.
• Radiotherapy for the moving patient not the inert plastic • Is there a genetic link to late radiation toxicity?
one; • Is there a role for a holographic display system could
• Focused ultrasound therapy; help clinicians to develop higher-quality radiation-
treatment plans?
• Understanding (predicting?) biological response to
therapeutic radiation; * Deduced from a trawl through the IOP Medical Physics Web
• Capitalising on the genome knowledge (how?).

• Use of nanoparticles and nanotechnology.

4:00pm
Plan for life and death

2007 man with
2009 man with chronic old-
Unusual avenues* 2….

Killed by wild animal chronic old age
diseaseage disease
100% (alive
and well
health and happy)
• Nanotechnology may image contrast agents, become drug Primitive
man
1950s man
Ideal
delivery vehicles, act as microsensors and measure locally

man
pH, temperature, drug level, dose, DNA damage?, cell

survival?
- E.g. super paramagnetic iron oxide (SPIO) to label cells by
transfection 0% (dead!)
- E.g. Gadolinium as a paramagnetic MRI contrast agent

20 40 60 80 A 100
Age (years)
• Quantum dots = nanocrystals of semiconductor material But what is this
coated with a shell ideal value A?
• Ultrasound microbubbles [1] “Primitive man” may have had no choice. He died young of accidents, malnutrition, poor housing
• The use of microbeams of radiation or….and probably didn’t have cancer at all;
[2] “1950s man” fought two World Wars, wore himself out working to age 65, smoked, had poor diet and
*From thoughts of Gerry Battista (Toronto) probably died soon after retirement. A relatively small fraction had cancer;
[3] “2009 man” has better housing, nutrition, care, working life etc and lives long but chronic ill health
including cancer may make QOL poor. An intermediate goal is to improve QOL for “cancer survivors”;
[4] We want to “live long and die quickly” (quote from Prof John Grimley Evans, gerontologist at Oxford
University)…but even if we solve cancer “something else will probably get us”…so to a “wish list”….
Accelerated Exponential Growth

Much progress in cancer research
has come (and will continue to e+γ(t) t
come) and will come through “It is news to no one that the rate of technical change in
communications has been accelerating in the past half
accelerated computer power and century. Time to reach 50 M users:
storage at lower cost (see next Radio 38 Years Data from a slide
slides)) Television 16 Years at ICCR by
PC 13 Years Gerry Battista
Internet 4 Years
Wireless Internet 1 Year
http://www.rice.edu/sallyport/2002/spring/features/president/infotech.html
Computer Growth Factors in 2005 Performance/Cost (MIPS per $1,000)
Component Doubling Time or

Half Life (Years)
Transistors per microprocessor 2 years
(Millions) Moore’s Law
IMRT Plan
Microprocessor Instruction Rate 1.8
Million per s (MIPS)
Performance/Cost Ratio 2 3D Plan
(MIPS per $1k)
TP-11
Calculations/Cost Ratio 0.9 PC-12
(calculations per second per $1k)
Rad-8
DRAM Memory 2 Data from a slide at
(Mbytes per dollar) ICCR by Gerry
Magnetic Disk Storage 1 Battista
(Mbytes per dollar) Data from a slide at ICCR
by Gerry Battista
Internet Speed (Mbytes/second) 1.2

4:00pm
Calculations per second per $1,000

Prof Lila Kari Professor & Canada
•In 1 cc DNA is the Research Chair in
computing power of all Biocomputing
the World’s current Department of
computers Computer Science
University of Western
1 MFLOP
•Ten (?) orders of Ontario London,
magnitude faster Ontario Canada N6A
•Present communication 5B7
via “ordinary 2002-2011
Data from a computers”
slide at Research interests
ICCR by Theory of computation: DNA computing
Gerry Discrete mathematics in relation to computer science
Battista Biological Computation: How does biology do information technology?
Biocomputing Laboratory
Awards
1991 for the best mathematics Ph.D. thesis in Finland
“Wish list” to work on for the 3rd Millennium

1 Gbyte per [1] Improving the diagnosis of disease
second
• More thorough screening programs will lead to a shift in stage profile

and greater focus on cancer survival;
• Diagnosis of disease will be based on a battery of imaging techniques
– normal population will be monitored by implanted biosensors; these
will be read by home-room-based sensors which will automatically
Data from a summon a doctor when a problem arises;
slide at ICCR by • 3D multimodality imaging will be routinely requested alongside blood
Gerry Battista tests, genetic tests and other tests;
• Telemedicine will become the norm; data will be stored centrally and
available anywhere in the world; doctors will not even need to be local
to the patient but could be called anywhere in the world by internet;
• The prevailing information will be functional not anatomical.
“Wish list” to work on for the 3rd Millennium “Wish list” to work on for the 3rd Millennium
[2] Improving the planning of radiotherapy [3] Improving the delivery of treatment
• Treatment planning will be patient-individualised based on measured
radiosensitivity and response to assays and functional imaging; • All treatment will include truly integrated imaging feedback into the delivery
• Functional and anatomical data will be merged; fuzzy logic may need to be process;
expanded to assign structures to imaging data; • Before each delivered fraction 3D imaging will inform to reposition the patient
• Tissue contouring will be automatic with minimal human intervention; accommodating intrafraction daily changes;
• By contouring all volumes a database of response versus delivered dose can be • 4D imaging throughout the treatment will guide corrections for intrafraction
prepared; motion;
• Treatment itself will become multimodality with combined photon, proton, ion • “Predict ahead” methods will be developed to overcome the latency between
therapy merged with brachytherapy, radionuclide therapy and even targetted gaining information on patient motion and correcting for it;
drug therapies and focused ultrasound. “Class solutions” will become a thing • C-arm and robotic linacs will deliver dose at a higher fluence rate; flattening
of the past; filters can vanish and be replaced by modulation;
• Multiple plans per patient will be prepared and compared to select the best; • Multiple robots (not just one!) will treat the patient just as multiple robots
• Planning will be 4D with multiple imaging throughout the course of treatment construct cars;
and re-adjustment of plans to accommodate changed functional status and • Every country will have at least one particle accelerator for cancer therapy to
geometry; act as a National Referral Centre and to gain experience to join the debate;
• Dose calculations will always be by MonteCarlo. All those quaint 20th century • Molecular genetics may combine with radiotherapy;
terms TAR,TMR,DD etc) will vanish;
• Will microbeam technology be useful?
• Dose will properly predict biological outcome.
• Can we really hope that heavy ion and proton facilities will be available
worldwide?

4:00pm
“Planning the Process” - What “conditions” are

“Wish list” to work on for the 3rd Millennium needed for these things to happen?
[4] Improving assessing response to treatment Medical Physicists need to be:
[1] educated at school to find science (which is difficult to do!) rewarding to continue;
• All patients will have tissue samples taken to enable treatment [2] led to understand that whilst specialising in medical physics is possible, many
outcome to be related to biological mechanism; medical physics breakthroughs have come from applying the physics from
• All patient dose, treatment outcome, tissue assay data will be stored mainstream areas; they need to be studied;
centrally for future recovery and analysis; [3] allowed enough “big me time” to do research properly although duties and service
are important for the day-to-day. It can’t be “fitted in odd moments”;
• Patients will fill in patient-specific symptom and response data to
[4] allowed to fail and follow blind alleys. Too much grant-driven research will kill the
refine the biological models of outcome;
process;
• Symptom data and dose data will be brought together to refine the [5] encouraged to avoid repetitive re-invention in medical physics, something all too
biological models of outcome; often seen at conferences;
• Post-treatment data collection will be the standard routine practice not [6] supported by National and International organisations (with education programmes)
the exception. Data will be coordinated through international trials. but not have imposed stifling training schemes and too many professional ladders to
climb;
[7] doing physics! Too many today do scientific business and scientific politics, in fact
anything rather than actually do fulltime physics.
[8] supported by Government, society and family.
A small
advertisement
if permitted
please:
13th Session : winter 2010
There are 6
weeks on
radiation
therapy,
protection,
medical imaging
and biomedical
computing at
this annual
Winter School at
Archamps
outside Geneva
www.cur-
archamps.fr/esi

9:30am
Contents
Quality Assurance and Verification • Introduction
for IMRT • Machine QA
• Patient Specific QA
• Current developments
Dr Catharine Clark
• Future trends
Introduction Key points

• IMRT is a complex technique • How and why IMRT QA fits into RT
• Requirement for all RT plans to be workflow
checked • Comparison of dose distributions
• Calculations can check TPS, but not – gamma index
delivery • General methods for introduction of
• This talk is about IMRT QA both for the complex techniques
patient plan and for the machine that will • The QA reduction challenge
deliver it
(IM)RT process (IM)RT process

• Immobilisation • Immobilisation
• Imaging • Imaging
• Volume delineation • Volume delineation
• Planning • Planning
• Independent verification • Independent verification
• Checking • Checking
• Transfer to treatment system • Transfer to treatment system
• Setup • Setup
• Treatment • Treatment
Friday 18th June 2010 1

9:30am
The QA pyramid The QA pyramid
Set-up 4 Daily Set-up 4 Daily
Per patient QA 3 Pre treatment Per patient QA 3 Pre treatment
MLC QA 2 Monthly MLC QA 2 Monthly
Basic linac QA 1 Monthly or other Basic linac QA 1 Monthly or other
Machine MLC QA Dynamic MLC QA

Dynamic delivery • Leaf positioning
– Leaf positioning
– Leaf speed The light field from
– Leaf stability a static MLC shape
– Leaf gap (effect of gravity) is checked against
a board with the
Based on tests by Chui et al. 1996 Med Phys 23(5) 635-641 pattern marked on it
which is positioned
at isocentre
Dynamic MLC QA Dynamic MLC QA

• Leaf Speed test
• 4cm sets of leaves

• A range of gaps
• At varying speeds
• Create different
intensities with same
• Leaf positioning verified at isocentre by light field dose rate
– Different preset positions
– Varied gantry angles

9:30am

• Leaf Speed test • Leaf Stability: Fence test
• An interruption tests the • Each bank of leaves moves to predefined

effect of acceleration and positions in the field creating vertical
deceleration of the ‘stripes’ of uniform intensity.
leaves on the intensity
profile • Beam ‘hold’ between control points
• Profiles used to check for • The width of these stripes determines the
effects positional accuracy

• Leaf Stability: Fence test • Leaf Stability: Fence test
Dynamic MLC QA Patient specific QA

• Leaf Gap: gravity • Individual fields (often gantry 0º)
• Absolute and relative dosimetry
• Tests width of the leaf • Accuracy of delivery
gap at different gantry • Methods: film, EPID, diode arrays
angles
• Entire treatments (clinical gantry angles)
• Ratio of dynamic • Absolute and relative dosimetry
output to open field • Integrated measurement
output is compared • Methods: ion chamber, film, TLD, gel, Monte Carlo
LoSasso et al. Med Phys 28(11), 2209 2001

9:30am
Patient specific QA Breast IMRT: before treatment

Field 1 Field 2 Patient Image
• ‘Simple’ IMRT such as Breast IMRT
• Before treatment
– MU verified as for standard treatment
– Field shapes verified on linac by comparison
with hard copy
• During treatment
– Acquire portal images
Field 3 Field 4 Cumulative intensity
EPID Verification Patient specific QA

EPID images acquired during treatment can • ‘Complex’ IMRT such as prostate or head
be summed to show the integral fluence. and neck IMRT (inverse planned)
• Measure individual dose points
• Analyse dose distribution
– Either individual field or combined
• Needed for both Step and Shoot and
Dynamic delivery methods
1st field 2nd field 3rd field 4th field Summed fields
Patient specific QA Patient specific QA : Dose Distributions

• Individual field
– Delivery accuracy
– More films / fields (split fields?)
– More analysis
– Earlier in an IMRT program
• Entire treatment
– Indication of dose distribution in patient
– Quicker and easier
– If errors occur, which field caused it?

9:30am
Patient specific QA : Dose

Patient specific QA : Individual fields
Distributions
Fields delivered with two carriage positions (Varian) • Choice of film
• Kodak XOmatV
– Lower dose
+ = – Better for individual
fields
• Kodak EDR2
120
– Higher dose
• Check that the two sections sum
100
– Linear response
80 Fade region
together correctly – Better for combined
Intensity
60 Total
Segment 1
• Dose distribution usually verified 40 Segment 2

fields
together 20
0
0 5 10 15 20
Position
Gafchromic EBT film Patient specific QA : Dose Distributions

+ Self developing therefore no processing
+ Insensitive to visible light
+ Flatter energy response
- Response dependent on time
- Quite expensive
0.4
0.3
Net OD
0.2
Coronal plane
0.1 – verifies all MLC leaves
0
0 1 2 3
Transverse plane
Dose (Gy)
– easy to compare with TPS
Patient specific QA : Dose Distributions Patient specific QA : Dose Distributions

• Diode or ion chamber arrays
• Easy to set up
• Methods of dose distribution analysis
• Quick to read out – Profile comparison
• Absolute and relative dose
– Isodose overlay
• Individual fields (clinical angles)
• Resolution of measurement points
• Distance to agreement (DTA)
– Dose difference
• % difference
– Gamma index
• DTA and % dose combined
2D 3D

9:30am
Patient specific QA : Dose Distributions Patient specific QA : Dose Distributions
Profile comparison
TPS TPS
Isodose
overlay
Film Film
Dose Gamma
difference map
Patient specific QA : Dose Distributions Gamma index

• Dose difference not good for high dose • Forms an ellipsoid of Δr 2 ΔD 2
gradients γrc , D c   
acceptance around each Δrtol2 ΔD tol
2
• Better to use distance to agreement (as for point

penumbra definition)
• Both high and low gradients exist in an IMRT • The gamma value at each
plan point is the minimum over
• Gamma index combines dose difference and all Δr and ΔD Δr
difference to agreement • Typically 3% and 3 mm

• Point is acceptable
• Low et al, Med Phys 25 656, 1998
• Depuydt et al, R&O 62(3) 309, 2002 agreement if  < 1
Gamma index Patient specific QA : Phantoms

• Geometric
– Easier to align
– Precise construction
– Use with multiple
dosimeters
• Anthropomorphic
– Inhomogeneities
– Less flexible for
Typical requirement for 95% of
measurement points
the points to have gamma <1,
within a given threshold – Not a model of our
patient

9:30am
Patient specific QA :
Patient specific QA : Dose point
Dose point measurement
• Ion chamber • Plan recalculated on a phantom
– Instant reading
– Everyone has one • No renormalisation
– Straight forward calibration
– Same leaf motions and MU as for patient
– Volume averaging
– Single point – Doses may be different from patient
• TLDs
– Multiple points
• Dose points and distributions compared
– Factor / readout for each chip between calculation on the phantom and
– Annealing
delivery to phantom
• Diode / Ion chamber arrays
– Multiple points
– Single plane
Patient specific QA : Dose point Summary of initial IMRT QA

• Homogeneous region of dose
• IMRT may require some additional machine QA
• Isocentre may not be the most suitable
• IMRT requires patient-specific QA to test both dose
• May need to adjust position of the plan on the
points and dose distribution
phantom for measurement point
• Tests depend on delivery technique and available
equipment
• Initial QA schemes should be intensive, but time
required will reduce as confidence grows
Current QA program and Portal Dose Image Prediction

developments Varis
• Portal dose image prediction

TPS
TPS
• Independent MU calculations Fluence map

• Back projected portal dosimetry EPID
• Monte Carlo calculations

Vision
Vision
• Reducing pre-treatment QA
Dosimetric Image Portal Dose Prediction

9:30am
Portal Dose Image Prediction

Head & Neck : 0.6
Independent MU calculations
PVI
0.5 PDIP
0.4
relative dose
0.3
0.2
0.1
0.0
Portal Dose Prediction EPID -10 -5 0 5
off_axis position (cm)
10
Prostate :
0.5
0.4
absolute dose (Gy)
0.3
0.2
0.1 PVI
PDIP
0.0
-6 -4 -2 0 2 4 6
Portal Dose Prediction EPID off-axis position (cm)
Development: Development: Monte Carlo

Back projected portal dosimetry • Currently used in some centres for dosimetry
verification along with measurements
• Backprojected from EPID
• Compared with TPS calculated plane • Ease of use increasing with speed of
computers and development of interfaces with
• Can be done in phantom or patient existing TPS
• Information about phantom/patient
• Problem in patients as daily changes (eg gas, • Independent MU calculation
bladder filling)
• Does not show practical delivery problems
• Original CT / daily CBCT
• Actual dose delivered to patient for a • Differences due to differences in photon
particular fraction algorithms
From Lawrence Livermore National Laboratory
Reducing pre-treatment QA Reducing pre-treatment QA

• For less complex IMRT (prostate) • More use of independent MU calculations
• Verification by MU calculation and pre- • Arrays with pre-loaded patient plan
treatment EPID • Greater use of EPID
• Full verification once a month per machine • Batching of patient QA plans
• Most complex and critical (or new sites)
IMRT still verified by measurement

9:30am
Future trends Key points

• Expansion of IMRT (30% by 2012 in UK) • How and why IMRT QA fits into RT
• Reduction of per patient QA workflow
– Reliance on independent calculation of MU • Comparison of dose distributions
• Real time delivery verification – The gamma index
– Portal imaging
• General methods for introduction of
– Back projection
complex techniques
• Image guidance, adaptive RT
• The QA reduction challenge
– IMRT must be able to adapt to techniques
– Appropriate QA

10:15am
Cochrane Shanks/Jalil Travelling Professorship

Overview
Cluj-Napoca, Romania
June 2010
• Definition of radiosensitivity/radiocurability
Combining Technical Radiotherapy with • Role of cytotoxic chemotherapy combined with
Chemotherapy and/or Targeted Drugs radiation in head and neck cancer
• Rationale for combining targeted drugs with radiation
Dr Kevin Harrington PhD FRCP FRCR or chemoradiation
Reader in Biological Cancer Therapies • Potential for integrating technical radiation
delivery/imaging advances and targeted drugs
• Radioprotection as a clinical strategy
Favourable Tumour Unfavourable Tumour (1)


70%
Complication-free
cure = 35%
40%
30% 30%
35%
Complication-free 20%
cure = 35%
Complication-free
cure
5%
5%
70 Gy 75 Gy
Radiation dose 70 Gy 75 Gy
Tumour dose-response curve Radiation dose (Gy)
Normal tissue dose-response curve Harrington and Nutting, Curr Opin Investig Drugs 2002
Unfavourable Tumour (2) Targeted Dose Escalation

80% 70%
Complication-free
cure = 65%
50% 40%
20%
Complication-free
cure = 35%
5% 5%
70 Gy 75 Gy 70 Gy 75 Gy
Radiation dose (Gy) Radiation dose (Gy)

10:15am
Radiosensitisation and Radioprotection Nomenclature of Combination Strategies

Induction Drug Radiation
Radiosensitisation Radioprotection Radiation

Concomitant
Drug Drug Drug
Adjuvant Radiation Drug
Radiation dose (Gy)
Commonly Used Drugs in Chemoradiation
• Cisplatin (CDDP)
• Carboplatin
• Hydroxyurea
• 5-FU/Capecitabine
• Mitomycin C
• Gemcitabine
• Taxanes
Survival Data Subgroup Analyses (1)

10:15am
Subgroup Analyses (2) Effects of Chemotherapy on Survival at 5 Years:

Pignon Meta-Analysis (2000)
Trial Category No. of Trials No. Patients Difference(%) P value

All trials 65 10850 +4 <0.0001
Adjuvant 8 1854 +1 0.74
Induction 31 5269 +2 0.10

PF 15 2487 +5 0.01
Other Chemo 16 2782 0 0.91
Concomitant 26 3727 +8 <0.0001
Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002.
Outcome Data
Progression-Free Survival
T
R
P
A
N F
D EUA Surgery
O P Daily Radiotherapy
M Hyperfractionated
I F
Z
E
TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750 CI- D1-5 Q 3 weeks x4
PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 4
Outcome Data
T Carboplatin - AUC 1.5

R
P Weekly
A
F
N Surgery
EUA
D
O P Daily Radiotherapy
M F
I
Z TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3
E PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

10:15am
Post-operative Chemo-RT Why Combine Radiation and New Agents?

459 pts 334 pts
• Radiation frequently fails to kill Doublings Cells Mass

Surgery Surgery all clonogens
• New targeted drugs unlikely to be
231 228 167 167 effective stand-alone therapies
• Smart targeting offers the
prospect of mechanistically
60-66 Gy/30-33F 66 Gy/33F favourable combinations
60-66 Gy/30-33F 66 Gy/33F
CDDP 100 mg/m2 d1, 22, 43 CDDP 100 mg/m2 d1, 22, 43
• Opportunities for additive,
• L-R control HR = 0.61 (95% 0.41-0.91) • 5 year PFS = 47% C-RT vs 36% RT
synergistic and independent
• 2-year L-R control = 82% C-RT vs 72% RT • OS HR = 0.70 (95% 0.52-0.95)
activities
• DFS HR = 0.78 (95% 0.61-0.99) • 5-year OS = 53% C-RT vs 40% RT
• Toxicities may not overlap
• OS HR = 0.84 (95% 0.65-1.09)
RTOG 9501 Cooper et al NEJM 2004; 350: 1937 EORTC Bernier et al NEJM 2004; 350: 1945
Rationale for Targeted Therapy plus RT Target Selection

Growth factor receptor targeting
• Overcome resistance mechanisms (non-cross resistance) Signal transduction pathway targeting
• Spatial co-operation p53 targeting Restoration of growth arrest

TRAIL
• Radiosensitisation Anti-bcl2
• Favourable alteration of tumour biology

– Reoxygenation
– Cell cycle redistribution
– Inhibit DNA repair Hypoxia targeting Anti-invasive agents (MMP)
Anti-VEGF targeting Chemokine blockade
– Impair (accelerated) repopulation Cell cycle targeting
Telomerase targeting
Cetuximab Plus RT Biological Contributors to Outcome
HYPOXIA REPOPULATION
INTRINSIC
RADIOSENSITIVITY
SC69
U2
Surviving fraction
0.1
SQD9
A549
A1847
0.01 SCC61
MCF7
0.001
Bonner et al. NEJM 2006; 354: 567 0 2 4 6

Dose (Gy)
8 10 12

10:15am
Guiding Use of Radiotherapy and Targeted Therapy Integration of New Technology and New Biology
Genotype Biological tumor identity card (proteo-genomic )
• New Technology
– Molecular imaging (pCT, DCE-MRI, PET)
– 3-D conformal RT
Tumor Rapid Intrinsic Critical
Phenotype – Intensity-modulated RT
Hypoxia? Proliferation ? Resistance ? Molecular
Target?
– Image-guided RT
High DNA repair Integrators of upstream
– Adaptive radiotherapy
Acute Chronic Hypoxia Rapid Proliferation
response?
Increase Accelerated
Inhibit DNA Repair p53: gene therapy, p53 – New targeted radioisotope therapies
Increase Chemotherapy specific drugs
oxygenation: oxygenation: Radiotherapy Gene therapy mTOR: Rapamycin
Vasoactive drugs Oxygen Inhibitor of DNA repair HSP90: Geldanamycin
(e.g. Nicotinamide) Hypoxic sensitizer Hypofractionation Proteasome inhibitor
(e.g. Nimorazole)
Increase DNA damage:
• New Biology
Concomitant Radiosensitizer Single molecular target?
Target Hypoxia:
Hypoxic cytotoxins
Chemo-RT Hyper/ultrafractionation
Dose escalation (3-DCRT,
bcr-abl: Imatinib
Ras activation: FTI
– Tumour profiling
(TPZ) EGFR: EGFR blockade
EGFR blockade IMRT, stereotaxy, isotope)
Gene therapy
Biological response
Concomitant chemotherapy – Response prediction
(e.g. inhibit HIF-1)
IMRT Boosts – New therapeutics
Anatomical vs Functional Imaging Biological Target Volumes
Geographical miss Radioresistance
Body outline
Body outline
Gross Tumour GTV

Volume
MRI/CT fusion PET/CT DCE-MRI, DW BTV BTV
MRI,
Perfusion CT
Avoidance of Geographical Miss Delivery of Boost to Radioresistant Volume
ANATOMICAL FUNCTIONAL
Interactions of Chemotherapy and Radiotherapy Improved Use of RT as an Executor Function

• Platins
– Formation of toxic platinum intermediates in the presence of ROS
Imaging Normal tissue sparing
– Radiation-induced increased cellular uptake of platin
– Inhibition of DNA repair • Proliferation
– Cell cycle arrest
• Hypoxia Tumour dose escalation
• 5-FU • Apoptosis
– Killing of radiation resistant cells in S phase • Oncogene RT Boost to Biologically
– Radiation induced expression of thymidine phosphorylase in dependence Relevant Populations
cancers
Addition of Targeted
• Gemcitabine (hydroxyurea) Agents
– Depletion of dNTP pools
– Inhibition of ribonucleotide reductase

10:15am
Radioprotection Amifostine: Clinical Experience

• 315 patients
• Approach arose from work in 1950s • RT 50-70 Gy at 1.8-2.0 Gy per day (radical or adjuvant)
to improve battlefield capability in • 75% of both parotid glands in RT high-dose volume

nuclear war
• Amifostine (200 mg/m2/day) vs no treatment

• Aim to spare dose-limiting tissues
• Open-label
from radiotoxicity
• Prototype compounds include

WR2721 Radioprotection
• Concerns about protection of cancer

cells
• Clinical studies focussed on

mucositis, xerostomia
Radiation dose (Gy)
Amifostine: Clinical Experience rhKGF: Clinical Experience
• BUT … read Brizel DM, Overgaard J. Lancet Oncol. 2003; 4: 378.

Spielberger et al NEJM 2004
rhKGF: Clinical Experience
• Recombinant human keratinocyte growth factor (N23-KGF) 60 g/kg week (x10)

• Standard RT (70 Gy/35#) or hyperfractionated (72 Gy at 1.25 Gy bd)
• Concomitant CDDP and 5-FU weeks 1 and 5
Spielberger et al NEJM 2004

10:15am
Toxicity Endpoints IMRT – Reducing the dose to the parotid gland in

tonsil cancer
Conventional IMRT sparing

• No significant benefit from rhKGF radiotherapy parallel left parotid
• No effect on PFS/OS opposed fields
Endpoints LENT SOM Subjective Xerostomia* rates

p=0.04 p=0.01 p=0.004 p=0.003
Primary: 86
83
– Incidence of subjective component of LENTSOM G2 74 71
xerostomia at one year after end of radiotherapy (“partial but CRT IMRT
62 60
persistent or complete dryness”)
Percentage
Secondary: ≥G2 39
– Acute and late radiation toxicity 29
– Overall survival, local control, pattern of recurrence

– Quantitative saliva flow measurements
n= n= n= n= n= n= n= n=
– Quality of Life 40 45 36 45 34 38 21 31
3 6 12 18
Months post treatment
* partial but persistent or complete dryness
Conclusions
• Head and neck cancer is a radiocurable tumour, but late stage

disease requires combination therapy
• Cisplatin-based concomitant chemoradiotherapy is a standard-of-
care
• The is a strong rationale for combining targeted drugs with radiation
or chemoradiation
• Integration of technical radiation delivery/imaging advances with
combination approaches offers prospect of benefit for patients
• Pharmacological radioprotection as a clinical strategy remains
unproven

11:30am
Better targeting of radiotherapy is

Head and Neck IMRT Evidence Base required
Dr Christopher M Nutting MD FRCP FRCR 1. To reduce radiotherapy complications and improve quality
of life for head and neck patients
Consultant and Reader in Clinical Oncology,
Clinical Director, Head and Neck Unit, Royal Marsden
Hospital & Institute of Cancer Research, Fulham Road, 2. To deliver higher doses of radiation to improve local or
London regional tumour control
3. To allow safe delivery of more potent chemoRT schedules

where acute and late toxicity are limiting factors
Potential Tools for targeted What is IMRT?

radiotherapy
1. Intensity Modulated Radiotherapy (IMRT)

Tumour
2. Image Guided Radiotherapy (IGRT)

Dose
3. Stereotactic Body Radiotherapy (SBRT)
Conventional Tissue Intensity Modulated

Radiotherapy Radiotherapy
Clinical examples
Head and Neck: Why IMRT?
Head and neck cancer is a highly attractive
IMRT site:
• Easily immobilised with limited organ motion
• Steep dose response curve for SCC supports
dose escalation strategies
• Complex target volumes and multiple OAR
close to targets

11:30am
Goals of RMH H&N IMRT Program Goals of RMH H&N IMRT Program
1. Reduce toxicity by improved dose
distributions to OAR 1. Reduce toxicity by improved dose
Site: Oropharynx – Parotid gland sparing distributions to OAR
Site: Oropharynx – Parotid gland sparing
2. Reduce local failure by improved target
volume localisation, and dose escalation 2. Reduce local failure by improved target
Site: larynx and hypopharynx organ preserving volume localisation, and dose escalation
chemoradiation protocols in Stage III and IV Site: larynx and hypopharynx organ preserving
chemoradiation protocols in Stage III and IV
Background (1)
PARSPORT
• Radiotherapy for head and neck cancer is
First Results of a Phase III Multi-Centre frequently curative, but at a price of significant
Randomised Controlled Trial of Intensity long term side effects
Modulated vs Conventional Radiotherapy in
Head and Neck Cancer: • Xerostomia is the most prevalent late radiation
PARSPORT (CRUK/03/005) toxicity of radiotherapy to the head and neck
region
C. Nutting, R. A'Hern, M. S. Rogers, M. A. Sydenham, F. Adab, • Xerostomia leads to reduced speech and swallow
K. Harrington, S. Jefferies, C. Scrase, B. K. Yap, E. Hall, function, accelerated dental caries and
on behalf of the PARSPORT Trial Management Group
osteoradionecrosis
Nutting et al Proc ASCO JCO 2009;27(2):799s
Background (2) PARSPORT Trial Design
• Intensity-modulated radiotherapy (IMRT) produces Head and neck cancer patients

complex dose distributions which can reduce the at risk of radiation induced xerostomia
dose to salivary glands (oropharynx/hypopharynx)
• Phase II data suggests that parotid-gland sparing
IMRT maintains saliva production Randomisation 1:1
• PARSPORT is a phase III randomised trial to test
this hypothesis Conventional Parotid-sparing IMRT
radiotherapy (CRT)
• PARSPORT is the only randomised trial of IMRT in
SCCHN 65Gy/30 fractions in 6 weeks - radical and post-operative R1/R2
60Gy/30 fractions in 6 weeks - post-operative R0

11:30am
Principal Inclusion Criteria Radiotherapy Planning and QA
• Histologically confirmed SCCHN • PARSPORT was the first multi-centre head and
neck IMRT trial in the UK
• Oropharynx or hypopharynx (T1-4 N0-3 M0)
• Detailed, rigorous, centralised QA program was
• High risk of xerostomia (i.e. estimated mean dose established
to both parotid glands >26Gy)
• Each centre had to submit specimen target volume
• Primary or post-operative radiotherapy definition and radiotherapy plans for approval prior
• WHO performance status 0-1 to recruiting patients*
• Neo-adjuvant chemotherapy was allowed • DVH data for tumour and normal tissues collected
(to be correlated with clinical data)
*Guerrero-Urbano et al Clin Oncol. 2007;19:604-13;

Clark CH et al Br J Radiol. 2009 Mar 30. [Epub]
IMRT – Reducing the dose to the parotid gland Endpoints

in tonsil cancer
Primary:
– Incidence of subjective component of
LENTSOM G2 xerostomia at one year after
end of radiotherapy (“partial but persistent or
complete dryness”)
Secondary:
– Acute and late radiation toxicity
– Overall survival, local control
Conventional IMRT sparing
– Quantitative saliva flow measurements
radiotherapy parallel left parotid – Quality of Life
opposed fields
Nutting et al Proc ASCO JCO 2009;27(2):799s Nutting et al Proc ASCO JCO 2009;27(2):799s
Patient and Tumour Characteristics Treatment Received
Number randomised 94 CRT n=47 IMRT n=47

Radiotherapy delivery as per protocol 43* 91% 46† 98%
Male 72%
Radiotherapy given as radical treatment 29 62% 38 81%
Mean Age (Range) years 58.4 (37.5-82.8) Mean (SD) radiotherapy dose PTV1 65 Gy (0.5) 65 Gy (0.4)
Ipsilateral Parotid mean (SD) dose 59 Gy (6.3) 45 Gy (10.6)
Median follow-up (IQR) months 31.9 (23.6-38.8) Contralateral Parotid mean (SD) dose 60 Gy (6.5) 26 Gy (6.8)
Radiotherapy given post-operatively 15 32% 8 17%
Site: Oropharynx 85%
Mean (SD) radiotherapy dose PTV1 64 Gy (2.3) 61 Gy (2.2)
Hypopharynx 15% Ipsilateral Parotid mean (SD) dose 61 Gy (5.0) 50 Gy (12.9)
Contralateral Parotid mean (SD) dose 57 Gy (10.3) 27 Gy (3.7)
AJCC stage I/II (T1/2, N0, M0) 23% Received neoadjuvant chemotherapy 19 40% 20 43%
AJCC stage III/IV (T3/4, N1-3) 77%
* 1 received IMRT due to coverage; 1 ineligible; 2 refused;
† 1 deviated due to rectal bleed


11:30am
Incidence of ≥G2 Acute Toxicity* LENT SOM Subjective Xerostomia* rates
Toxicity CRT IMRT p p=0.04 p=0.01 p=0.004 p=0.003

(Graded according to CTCAE v3) n=44 n=45 (chi-squared)
Mucositis clinical 98% 91% 0.18 86
83
Dysphagia 98% 87% 0.05 74 71
Salivary gland 95% 80% 0.03 62 60
Rash 93% 76% 0.02 CRT
Percentage
IMRT
Dry mouth 91% 71% 0.02 ≥G2 39
Pain 89% 76% 0.11 29
Mucositis functional 86% 73% 0.13

Fatigue 41% 76% <0.01
n= n= n= n= n= n= n= n=
Weight loss 34% 44% 0.32 40 45 36 45 34 38 21 31
Hair loss 18% 29% 0.23 3 6 12 18

* partial but persistent or complete dryness
*during and up to 8 weeks post RT
RTOG Subjective Salivary Gland toxicity ≥G2* Incidence of LENT SOM ≥ G2 at 12 months
p=0.03 p=0.001 p=0.05 P<0.001 Toxicity CRT IMRT p (exact)

(n=34) (n=39)
83
81
78
Mucosa 15% 23% 0.55
64
Skin 15% 8% 0.46
56
Percentage 47
CRT Mandible 12% 13% 1.00
≥G2 41 IMRT
Oesophagus 6% 13% 0.44
20
Teeth 6% 3% 0.59
Ear 3% 0% 0.47
n= n= n= n= n= n= n= n=
41 45 36 45 33 37 21 30 Larynx 0% 5% 0.50
3 6 12 18 Spinal cord 0% 3% 1.00
*Moderate or complete dryness of mouth
poor or no response on stimulation
Incidence of RTOG ≥G2 at 12 months Overall Survival

1.00
Toxicity CRT IMRT p (exact)

(n=33) (n=37)
0.75
Proportion alive
Mucous membranes 12% 8% 0.70

1 year overall survival (95% CI):
Subcutaneous tissue 6% 5% 1.00 CRT (n=47): 90.8% (77.3 – 96.4)
CRT
0.50
IMRT
Joint 6% 3% 0.59 IMRT (n=47): 93.6% (81.5 – 97.9)
Oesophagus 3% 10% 0.37

0.25
Hazard Ratio (IMRT:CRT) = 1.05 (0.38 to 2.90)

Skin 3% 6% 1.00
0.00
Bone 3% 3% 1.00 0 3 6 9 12 15 18
Months from end of treatment
Larynx 0% 0% - n events/at risk
Spinal cord 0% 0% - CRT 0/47 1/44 3/40 3/32
IMRT 0/47 1/47 2/45 5/34

11:30am
Loco-Regional Progression Free Survival (LRPFS) Conclusions

• IMRT significantly reduces odds ratio of subjective
1.00
xerostomia by about 50% for patients with

Proportion progression free
pharyngeal cancers
0.75
1 year LRPFS (95% CI):

CRT • Acute radiation fatigue was more prevalent with
0.50
CRT (n=47): 88.0% (73.5 – 94.8)

IMRT (n=47): 87.3% (73.9 – 94.1)
IMRT IMRT possibly due to more normal tissue irradiation
0.25
Hazard Ratio (IMRT:CRT) = 1.59 (0.67 to 3.80)

• Further follow-up is required to determine the
maximum benefit of this technology
0.00
0 3 6 9 12 15 18
Months from end of treatment • These data support the adoption of IMRT as the
n events/at risk
CRT 0/47 0/45 5/36 2/28
standard of care for head and neck cancer patients
IMRT 0/47 2/46 4/41 6/30
Nutting et al Proc ASCO JCO 2009;27(2):799s Nutting et al Proc ASCO JCO 2009;27(2):799s
Nasopharynx: parotid gland sparing IMRT Nasopharynx: parotid gland sparing IMRT
• QoL reduced between baseline and 2 months, then
• Pow et al IJROBP 2006
increased similarly over time in both groups (NS)
• Small randomised trial of 51 patients with T2 N0/1 M0
• HN35: IMRT patients had improved dry mouth
nasopharynx cancer: CRT vs IMRT swallowing and sticky saliva scores (p≤0.01)
• Stimulated and unstimulated saliva flow was greater in
• No correlation was seen between saliva flow rates and
IMRT patients starting 2 months after treatment and
QoL
increasing over time (p=0.002)
• HN35: Saliva flow rate did correlate with speech, dry
• Recovery of parotid flow to at least 25% of pre-
mouth, and sticky saliva domains
treatment levels was 83% with IMRT, and 10% with
CRT
• QoL domains tested with QLQ 30 and HN35 over initial
12 months
Pow et al IJROBP 2006
Goals of RMH H&N IMRT Program
1. Reduce toxicity by improved dose

distributions to OAR
Updated Results of Phase I/II Dose
Escalation Trial of Chemo-IMRT in
Site: Oropharynx – Parotid gland sparing
Advanced Laryngopharyngeal Cancer
2. Reduce local failure by improved target
volume localisation, and dose escalation
Site: larynx and hypopharynx organ preserving
chemoradiation protocols in Stage III and IV

11:30am
Typical approach for locally advanced

Larynx/Hypopharynx Conventional vs IMRT
PTV1: Gross primary

tumour ± involved
nodes = Radical Dose
of 70Gy 35F
PTV2: Elective nodal

areas = Elective dose of
50Gy 25F
Represents approx 50% reduction of vol of tissue irradiated to radical dose
RMH Dose escalation trial Doses Inhomogeneous IMRT dose distribution:

theoretical risks and benefits
PTV 1 PTV 2
•High total dose (D)
Dose level 1 63.0Gy 28# (2.25Gy) 52Gy 28#
BED10Gy 66.6, BED3Gy 110.3 (1.85Gy) •Acceleration with hypo-
Log cell kill 10.12 N/A fractionation to primary: Care
Dose level 2 67.2Gy 28# (2.4Gy) 56Gy 28# with low α:β OAR in PTV 1
BED10Gy 72.8, BED3Gy 121.0 (2.0Gy) •Low fractionation sensitivity
Log cell kill 11.06 N/A
of microscopic disease
Conventional 70Gy 35# (2Gy) 50Gy 25# •Single-phase plan for 28F
70Gy 35# BED10Gy 74.1, BED3Gy 116.67 (2Gy)
Log cell kill 10.26 N/A •10-15 minutes to deliver
1.85Gy/# 2.25Gy/# x28#
•No electrons
Dose 51.8 and 63.0 Gy
Fowler 2009: Work in progress
Induction and Concomitant

Phase I/II Trial Design Chemotherapy
• n = 15 for each dose level initially, expanding to 30 Concomitant Chemotherapy

Induction chemotherapy
•Main expected toxicities were Late: cartilage necrosis, Cisplatin 100/m2 d1 + 28
Cisplatin 80/m2 d1
oesophageal stricture
5FU 1000mg/m2 d2-5
•Phase I stopping rules: If 0/15 have G3 toxicity then 20%
risk is excluded with 95% power. If 1/15 have G3 toxicity
then expand cohort to 30
Ind 1 Ind 2 IMRT 28 #
Carboplatin AUC 5 substituted if Cisplatin contraindicated
Bhide et al BJC 2008

11:30am
Results: Demographics ACUTE RADIATION

Dose level 1 Dose level 2 DERMATITIS
Number 29 31
Median Follow up 49 (35-78 36 (17-62)
(months) 100.0%
Mean treatment time:
Male 79% 77%
•63.0Gy cohort: 393 days Median Age 58 63 75.0%
•67.2Gy cohort: 381 days

Larynx 17 16 G3 63.0Gy
Hypopharynx 12 15 50.0%
G3 67.2Gy
G2 63.0Gy
NO TREATMENT BREAKS I 1 0
G2 67.2Gy
II 1 0 25.0%
97-100% COMPLIANCE III 12 16
WITH INDUCTION + IVA 13 15
COMCOMITANT IVB 2 0 0.0%
CHEMOTHERAPY 1 2 3 4 5 6 7 8 9 10 14
PS
0 83% 97%
1 17% 3%
Guerrero-Urbano 2008 R&O
Guerrero Urbano et al 2008
RADIATION INDUCED
ACUTE TOXICITY: NCI CTC v.2.0 scale
DYSPHAGIA
Incidence of acute G2 and G3 toxicity
Prevalence of acute G3 dysphagia
63.0Gy cohort 67.2Gy cohort
100.0%
G2 G3 G2 G3
80.0%
G3 dysphagia, %
63.0Gy cohort: Spearman’s Dermatitis 66.7% 20% 46.7% 20%

rank correlation coefficient 60.0%
67.2Gy cohort
between mucositis and 63.0Gy cohort Mucositis 33.3% 66.7% 46.7% 40%
40.0%
dysphagia
0.6 (p=0.02) 20.0%
Dysphagia 20% 66.7% 13.3% 86.7%
0.0%
1 2 3 4 5 6 7 8 9 10 14 Pain 46.7% 26.7% 53.3% 40%
Follow-up (weeks)
Xerostomia 60% 0 73.3% 6.7%
Guerrero-Urbano 2008 R&O Guerrero-Urbano 2008 R&O
Late Normal Tissue Toxicity at 1 year

Dose escalation trial results at 2 years
Dose Level I (63 Gy/28 #) Dose Level II (67.2 Gy/28 #)
Organ Grade Grade Grade Grade Grade Grade DL1 DL2

I II ≥ III I II ≥III
Median Follow up 51M 36M
Oesophagus 25% (5) 0% 5% (1) 60% (15) 29% (7) 8% (3)
Local control 71% 86%
Salivary Gland 43% (9) 9% (2) 0% 54% (9) 8% (2) 0%
Loco-regional control 68% 82%
Larynx 33% (7) 24% (5) 0% 58% (14) 7% (4) 0% Loco-regional PFS 64% 78%
Subcutaneous 14% (3) 0% 0% 30% (7) 7% (2) 0% DFS 62% 78%
Skin 19% (3) 5% (1) 0% 12% (3) 0% 0%

Larynx preservation rate 89% 96%
Overall survival 72% 74%
Mucosa 43% (9) 0% 0% 30% (7) 0% 0%

11:30am
Outcome: Survival Other dose escalation results

event_lr
100
Survival Function
90
1.0
80
• Madani et al IJROBP 2007;68(1) 126-35
Survival probability (%)
70
– Dose escalated PET+ve regions

.8 60
group
50 0
1
.5
40
30 – 72.5Gy and 77.5Gy in 32 fractions
20
10
– High levels of local control were seen
– 2/18 in DL2 had G4 toxicity, 1/18 fatality
Cum Survival
.3 0
0 10 20 30 40 50 60 70
– We are close to the dose which may cause fatal

Survival Function Time
0.0 Censored Number at risk
0 12 24 36 48 Group: 0
Group: 1
29 25 16 10 7 5 2 1 mucosal necrosis
Time to death- months
31 24 13 10 7 0 0 0
– Reductions to the GTV are probably needed to
deliver such high doses
Overall Larynx preservation rate 89 vs 96% at 2 years – Patients should be treated within the context of
clinical trials.
Loco-regional 68% vs. 82% at 3 years
Proposed Phase III Trial Schema Conclusions
Male or
female Radiotherapy - Experimental Arm
• Dose escalation with IMRT is possible at
patients aged
18-70 with
locally
67.2Gy in 28 fractions to the involved
site and nodal groups
56Gy in 28 fractions to nodal areas at
the expense of increased acute toxicity
C
• Late radiation toxicity at 1-3 years is not

advanced O risk of harbouring microscopic disease.
squamous cell Complete
N
cancers of the baseline R
S
enhanced and is similar to reported

larynx or Quality of
E
hypopharynx Life
N Radiotherapy - Conventional Arm
requiring T
definitive
treatment with
chemo-
65Gy in 30 fractions to involved site
and nodal groups
54 Gy in 30 fractions to nodal areas at
contemporary series
radiotherapy
• Significant increases in local tumour

risk of harbouring microscopic disease.
control are seen in this small phase II trial

Induction chemotherapy
[Optional by centre]
• A randomised trial is proposed by the H&N

Patients may receive a
maximum of 3 (21 day) cycles
All patients will receive
concomitant platinum 100mg/m2
IMRT group and will open Q3 2010
of platinum based induction on day 1 & 29 of their RT schedule
chemotherapy prior to
radiotherapy
Targeting with PETCT

• Comparison of
CT, MRI and
FDG-PET with
surgical specimen
• FDG-PET closest
to pathology
CT alone PET alone PETCT
Newbold et al 2008 Daisne et al, Radiology 2004

11:30am
Validation of DCE-MRI
Targeting hypoxia with DCE-MRI with hypoxia staining
• Hypoxia confers radiation resistance on • Pimonidazole fixation

and CA9 expression
cancer cells were detected using
• Hypoxia represents a potential target for an IHC technique
radiation dose intensification
• Path section matched
• Several techniques potentially allow to image slice
imaging of hypoxia for radiation targeting
• DCE-MRI, dCT, CuATSM, Misoonidazole • ROIs transferred
between path and
images
DCE-MRI Overall Conclusions
• Targeting of radiation can be achieved with

advances in radiotherapy technology
• Targeted IMRT can reduce xerostomia, the most
common toxicity of RT
• Targeted IMRT can increase tumour control by
dose escalation
• In the future, new targets will be developed
through functional imaging
• More clinical trials are required to test the clinical
benefits of these technologies in patients
Newbold et al 2008

12:15am
Pitfalls
Common pitfalls in head and  Technique

Benign disease
neck cancer imaging 
 Large volume disease

 Post treatment
Julie Olliff  Radiotherapy change
University Hospital  Appearances post surgery
Birmingham
 Recurrent disease
UK
 Nodal disease
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP
E
S
H
Technique Communication with clinician

CT
 Larynx - angle or reconstruct parallel to vocal
cords  Do not presume that every lesion is
 Gentle respiration
malignant – communication important
 No swallowing
MRI  Post biopsy change
 Choice of sequence–
sequence–eg.dessicated secretions,  Vocal cord stripping for dysplasia
slow flowing blood, blooming from para-
para-
magnetic substances on GE sequences
 Use of faster sequences eg BLADE for motion
artefact
Large volume disease Post radiotherapy change

 symmetric thickening of the epiglottis,
ary-
ary-epiglottic folds and false cords –
 May prolapse into/obliterate hypopharynx within 3 months of completion
 posterior pharyngeal wall thickens and
simulating invasion mucosa enhances
 Would alter surgery  retropharyngeal space oedema
increased attenuation of paralaryngeal
 Usually not a problem - endoscopy 
fat - within 2 months
 Symmetric thickening of subglottic fat
seen in 80%
 thickening of anterior and posterior
commissures-
commissures- late changes 7- 7-14 months
Mukherji and Weadock EJR2002;44:108

12:15am
Surgery Post tracheostomy

 Post biopsy
 Tracheostomy  Swelling and surgical emphysema will
distort soft tissues
 Treatment of primary tumour
 Partial and total laryngectomy
 Beware overstaging subglottic extension
 Kelsch and Patel Seminars in Ultrasound, CT  Subglottic tissue should be in continuity with
and MRI 2003;24:147-
2003;24:147-156 tumour
 Small bowel interposition  Cricoid cartilage involvement
 Surgical flaps
 Wester et al AJR 1995;164:989-
1995;164:989-93
 Surgicel
Surgery – treatment and staging of

Total laryngectomy
nodal disease - Neck dissection
 Loss of thyroid and cricoid cartilages and  Asymmetry/absence of the submandibular
hyoid bone gland
May give rise to “palpable mass”
mass” and may be
 Oesophagus has rounder configuration-
configuration-

interpreted as disease by radiologist!
walls 2-
2-3mms thickness
 Lack of fat plane around the vascular
 Variable resection of thyroid – remaining compartment
 May be mistaken for recurrence  Denervation of the accessory (shoulder
dysfunction) and hypoglossal nerves
Denervation following neck Flaps

dissection
 22/174 patients following RND abnormal  Knowledge of appearance of flaps
and/or hemiatrophy on the side of the  Nodes within flaps
tongue operated on Denervation of flaps-
 flaps- abnormal
 No evidence of tumour recurrence and no enhancement may be mistaken for
evidence of soft tissue recurrence along recurrent disease
course of hypoglossal nerve.
Murakami et al AJNR 1998;19:515

12:15am
Foreign bodies Recurrent disease
 Clips  Cartilage
Sclerotic foci are more likely to represent reaction to
 Thyroplasty – treatment of vocal cord 
surgery. Obvious cartilage destruction by a soft tissue
paresis mass = tumour
 Teflon  Soft tissue mass
 Gortex  Mass> 10mm have 63% probability of being
malignant. (Maroldi
(Maroldi et al). Soft tissue thickening
 Silastic
>1mm at anterior commissure suspicious, but beware
post radiotherapy change and post op granuloma!
granuloma!
Neck nodes Conclusion
Central necrosis – pitfalls  Ensure good technique

 Fatty hilar metaplasia  Good clinical history
 Usually at periphery of node  Image before intervention
 If central may be indistinguishable from  Radiologists and clinicians need to work
necrotic malignant node very closely together
 Usually in response to chronic nodal infection
 Thrombosed IJV
 Other mimics

Head and Neck Conformal Therapy and IMRT Course

Enviado por

Dados do documento

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Head and Neck Conformal Therapy and IMRT Course

Enviado por

Direitos autorais:

Formatos disponíveis

THE ROYAL COLLEGE OF RADIOLOGISTS

THE INSTITUTE OF PHYSICS AND ENGINEERING IN

Head and Neck Conformal therapy and IMRT Course

The Imaging Centre at St Thomas'

9:15 Lecture 1: The 21st Birthday Party for Intensity-Modulated

10:00 Lecture 2: Clinical application of conformal therapy and IMRT

10:45 Lecture 3: Practical considerations for conformal therapy and

11:15 -11:45 Break

Session 2 Imaging and planning

12:30 Lecture 5: IMRT treatment planning basics

1:00-2:00 Lunch Break

Session 3 Practical session (1)

Clinical Target Volume Definition CN/KJH

4:00-5:00 Topic Lectures

4:00 Lecture 6: Interfaces between classical and molecular

9:45 Lecture 8: FDG-PET in head and neck cancer

12:30 Lecture 11: Verification of Treatment Delivery: Role of imaging

1:00-2:00 Lunch break

Session 3 Practical session (2)

Clinical Clinical plan assessment CN/KJH

Radiology special topics

PET in Oncology: FDG and Beyond S Rankin

4:00-5:00 Topic Lectures

4:00 Lecture 12: Combatting cancer in the third millennium: the

9:30 Lecture 13: Quality Assurance and verification for IMRT

10:15 Lecture 14: Combining technical radiotherapy with

1:00 Closing remarks

2 Radiation Oncologists: Dr Nutting, and Dr Harrington, Royal Marsden Hospital and

1 Treatment Radiographer: Miss Helen McNair

2 Oncology Diagnostic Radiologists:Dr Julie Olliff, Birmingham UK and Dr Sheila

Kevin Harrington is Reader in Biological Cancer Therapies and Honorary Consultant in

Helen was pleased to return by invitation to Australia in 2006 as a keynote speaker at

She is a member of the British Institute of Radiology Oncology committee and is

Dr Christopher M Nutting BSc FRCP FRCR MD ECMO

Dr Nutting is Consultant and Reader in Clinical Oncology at the Royal Marsden

He trained in Oncology at the Royal Marsden Hospital and St Bartholomews Hospital,

Dr Sheila Rankin FRCR

Dr Rankin is a consultant radiologist at Guy’s & St Thomas Foundation trust. Her

3D Conformal Radiation Therapy

Steve’s books look like:

One cannot really

The “Royal” in the Royal Marsden Hospital, London, UK

Even I can’t remember this far back

1st medical physicist at RMH Major

Joint Department of Physics The development of Intensity-modulated

Wednesday 16th June 2010 1

Professor Anders Brahme

1895 The x ray was discovered on November 8th in Germany by

The London Hospital (I think) in 1906

Synchronous aperture “Concave

Wednesday 16th June 2010 2

Overview of 114 years of radiotherapy

Minimise unwanted dose to

Note increased sparing of normal tissue

The Brahme/ Scanditronics MLC of 1984

Why do we perform Intensity

An example of why we want a concave dose distribution

Wednesday 16th June 2010 3

An 2nd example of why we want a concave Frame sequence

Message: Note the sparing

Early milestones in inverse

(i) <1920s: no planning,

Wednesday 16th June 2010 4

Dramatic news in Geneva. October 20th 1992