head and neck conformal therapy and imrt course

The Imaging Centre at St Thomas'The Imaging Centre at St Thomas'

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

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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

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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

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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

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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!]).

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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 team1. 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: [email protected]

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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

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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:

LECTURES:

SLIDE HANDOUTS

Day 1 Session 1 Lecture 19:15am

1Wednesday 16th June 2010

Steve Webb

Institute of Cancer Research

(University of London)

and Royal MarsdenHospital, UK

The 21st Birthday Party for Intensity-Modulated Radiation Therapy (IMRT); 21 years from 1988-2009;

from concept to practical realityRomania June 2010

One cannot really imagine one without the other. There is

great strength in this unity

Joint means……….I come from the Institute of Cancer Research and the Royal Marsden Hospital, London, UK

Even I can’t remember this far back

1st medical physicist at RMH Major Charles Phillips (gentleman scientist)

Sheffield doctor: William Marsden

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

Joint Department of Physics

• About 150 physicists, roughly 50% NHS (RMH) employees, 50% university (ICR)

• Mix of research, clinical service, teaching and business – no hard boundaries

• Excellent interaction with key clinicians• Teams: radiotherapy physics, nuclear medicine

physics (imaging and therapy), ultrasound and MR physics, x-radiology and protection services

• About 25 PhD students at any one time• Heavily grant supported from CR-UK, EPSRC,

industry,….EU

The development of Intensity-modulated radiation therapy (IMRT)

IMRT has made a major clinical impact improving the precision of delivery of high dose

to tumours while sparing organs at risk.

How has the field reached the present position?



How IMRT works

You see the 9 modulated beams and the corresponding conformal dose map built up.

Professor Anders Brahme

1988 famous paper on inverse planning

Series of lecture tours “assisted” IMRT elsewhere in key centres

(DKFZ, MSKCC, ICR-RMH…….) 1982 Brahme et al discussed inverse-planning for a fairly special case of rotational symmetry.

Prehistory

Hindsight is wonderful.

What came before 1988?

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

The London Hospital (I think) in 1906

This is (nearly) the principle of IMRT

Synchronous aperture shaping and shielding by Proimos.

“Concave isodoses”in 1961!

1970s The Royal Free Hospital built the “tracking cobalt unit” and MGH Boston did similar tracking with a linac.



1950s Takahashi first discussed conformation therapy.The Gscheidlen MLC patent of 1959

&

The Brahme/ Scanditronics MLC of 1984 (ESTRO3) 18961896--1950 1950s 11950 1950s 1990990--2010s2010s

Traditional cross-fire therapy Rotation therapy Conformal therapy

including Intensity Modulated Radiation Therapy (IMRT)

Minimise unwanted dose to normal tissues

Tumour

Overview of 114 years of radiotherapy

Note increased sparing of normal tissue

Why do we perform Intensity Modulated Radiation Therapy

(IMRT)?

prostateprostate

rectumrectum

bladderbladder

An example of why we want a concave dose distributionProstate and Pelvic Node Clinical IMRT Trial. A typical

transaxial section looks like this.



Head & Neck

Frame sequence

1) Pink: body contour

2) Dark green: thyroid

3) Light green: nodes

4) Switch off body contour

5) Yellow cord

6) Grey: oesophagus

Message: complex planning case!

Courtesy of Mike Partridge

An 2nd example of why we want a concave dose distribution

PTV195%90%

PTV295%90%

Head & Neck[movie progresses from superior to

inferior]

Note the sparing of the cord (orange) by highly concave isodoses

Head and neck IMRT patientHead and neck IMRT patient

((transaxialtransaxial (left); coronal (right))(left); coronal (right))

Parotid sparing of a tonsil IMRT patient who is beingParotid sparing of a tonsil IMRT patient who is being

treated to 65 treated to 65 GyGy to the primary PTV and 54 to the primary PTV and 54 GyGy to the nodes in 30 fractions.to the nodes in 30 fractions.

The spared parotid can be seen at the top right of the image on The spared parotid can be seen at the top right of the image on the right.the right.

phase 3 trial randomised between conventional RT and IMRT. phase 3 trial randomised between conventional RT and IMRT.

PTV195%90%

PTV295%90%

Note sparing Note sparing of the cord (1of the cord (1stst

yellow) and yellow) and one parotid one parotid (2(2ndnd yellow)yellow)

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,

Early milestones in inverse planning



Symbolising the Symbolising the essence of IMRTessence of IMRT

11th Session: winter 2008

Dramatic news in Geneva. October 20th 1992

– the World’s 1st truly IMRT delivery equipment

Mark Carol at 12th ICCR Conference 1997 [on roller blades]

The NOMOS MIMiC

1992 Carol first showed the NOMOS MIMiC and associated PEACOCKPLAN planning system CORVUS).

1992 Mark Carol: MEDCO and NOMOS

• 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 Boyer made the first IMRT s-&-s delivery in Houston using a 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)

How IMRT works

You see the 9 modulated beams and the corresponding conformal dose map built up.



How to make a 2D complex modulation by leaf sweep and step-and-shoot with a MLC

Leaves move only one way; radiation off between moves

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

DeutschesKrebsforschungszentrum

(German Cancer Research Center)

Im Neuenheimer Feld 280

Dynamic multileaf collimator (dMLC) IMRT delivery

• Technique

• 3 groups in 1994 (Stein et al / Spirou and Chui / Svensson et al – all had the same maths.

• From “one-off” to market leader (?) – commercial thrust via Varian, Elekta, Siemens…

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

•Disclaimers!

•Reviewers of history tread dangerously.

•True versus amateur historians.

•Agreement of major landmarks vs controversy on the detail – A.N. Other may tell the story differently.

My view is not the only one

•Everything important has happened in the last 21years.

•So vast majority of pioneers are (i) alive (ii) still working

•If I mention key names do I make instant enemies? I hope not

1993 Tomotherapy (the Wisconsin machine) first described by Mackie. (August 2002 the first clinical treatments)



(Swerdloff) Collimator as in NOMOS MIMiC and in Wisconsin Tomotherapy machine

Prostate tomotherapy delivery

The motion of internal markers is detected by x-rays; motion of external markers is

detected by infrared. Motions are correlated every 10s. Monitor of external

markers by i.r. then translates to movement of internal tumour markers in

almost real-time and this is fed back to the robot.

Cyberknife

Clinical implementation of IMRT by the Multi-Leaf Collimator (MLC)

method in London, UK• ICR/RMH 1st patient Sept 20th 2000 at Sutton

(prostate + pelvic malignancy). Patients now about 300+.

• First prostate and node patient at Chelsea July 2001.

• First H&N IMRT was treated in Chelsea in April 2002.

• First H&N treated in Sutton in August 2003.

• Memorial Sloan Kettering Cancer Centre 1995->.

• Evidence for efficacy.

0

10

20

30

40

50

60

70

2000 2001 2002 2003 2004 2005 2006 2007 2008

PPN H&N

LUNG PAED

Inverse Planned IMRT TreatmentsThe Royal Marsden (Sutton)

Patient numbers

Planning Systems used: 2000 Corvus; 2001 – 2003, Helax;

2004 – 2008, Philips Pinnacle (DMPO), except Lung: AutoBeam + Pinnacle.

CT based treatment planning increased from 400 to 2100 patients per year over this period. Forward planned, segmental IMRT for breast, prostate and rectum tumour sites in 2008: 150 patients per year.

PPN total 151

H&N 76

Paed 9

Lung (VMAT) 4

Courtesy of Jim Warrington

•Total number treated: 488

•212 PPN

•259 H&N

•17 Sarcoma

•Significant increase in 2008 due to change in QA from measurement to calculation based MU verification

From Margaret Bidmead

Number of patients treated with IMRT at RMH London(July 2001-March 2010)

3 8 15 17 17 22 17

5637

200

811 15

2747

56

60

1421

0

20

40

60

80

100

120

140

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Year

Nu

mb

er

Sarcoma/other

Head & Neck

Prostate & Nodes



Inverse planning and IMRT at DKFZ-Heidelberg (slide courtesy of Wolfgang Schlegel)

Start of IMRT treatment at dkfz: 1997

IMRT patients at dkfz

0

50

100

150

200

250

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

year

patients

0

50

100

150

200

250

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Inverse Planned IMRT Treatments dkfz, Heidelberg

Patient number Prostate 154 Lung Cancer/Pleuramesothelioma 98Head and Neck 280 Chordoma/Chondrosarcoma 148Meningeoma 98 Pancreas 91Mamma-Ca 25 Oesophagus-Ca 43others 334

New technology =

[1] New technology for image guided radiation therapy;

[2] New technology for IMRT delivery(these two are today intrinsically linked)

IMRT and IGRT What is Image Guided RadiationTherapy (IGRT)?

All radiotherapy techniques that rely on the use of (generally 3D or 4D) images

To solve what problems?

At planning stage: (1) Disease staging and determining the GTV and CTV, (2) Assessing change of target, need to re-plan, adaptive therapy

Pre- (each) treatment fraction: Positioning patient correctly (interfraction motion correction)

During each fraction: Intrafraction motion correction by either (1) gating, (2) breath-hold (3) tracking

Post-therapy: Assessment of response

What technology can assist?…and is it available in the UK?

• Target volume definition

• Treatment planning

• Beam delivery verification

• Interfraction motion

• Intrafraction motion

• Intrafraction correction

• PET, SPECT, MRI,, CT

• kV x-ray film

• MV film, EPID, MVCT

• Optical markers, Ultrasound, MVCT, kVCT, Implanted markers (x ray opaque or magnetic)

• Optical markers, kV stereo-imaging,Ultrasound, Implanted markers (x-ray opaqueor magnetic)

• Breathing control (audio-visual; held-breath; spirometry), Linac gating, Tracking MLC

[In UK: Widely clinically available; clinically available in some Centres; mainly “under development”]

New Technologies to deliver IMRTFirst 3 allow inter-fraction position adjustment

[1]* “Viewray”: MRI and Co60 IMRT combined in one integrated unit (3 Co sources; Dempsey group Florida)

[2] † MRI and linac combination (Utrecht; Lagendijk)

[3]#Tomotherapy; slice-based/helical (Nomos/TomotherapyCorporation)

Next 3 allow intrafraction motion correction

[4]* Dynamic “breathing leaves” MLC

[5]#Robotic IMRT with Synchrony imaging (Sunnyvale: Accuray)

[6]#Dynamic-shaping of fields via double-bank MLC and EPID on circular rails (TrackBeam)

_____________________________________________* Concept only † In progress since 2000 # Available now



VMAT

Courtesy of James Bedford and Jim Warrington

Can vary:

[1] gantry speed;

[2] fluence output rate;

[3] MLC field shapes;

[4] MLC orientation

all dynamically

No-one really knows a general theory. Sometimes (but not always; often the reverse) can get better conformality with fewer MU.

Fluoroscopy to show moving lung / lung tumour

Same patient

Different patient

(courtesy of Helen McNair)

Note the variability of motion

Motion and its variability are the

enemy!

Synchronised Delivery

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

MLC motion

MLC motion

For the future………..

Solutions to tumour motion in NSCLC RT

technologyintensive

patientintensive

regular breathing

voluntary breath hold

imposed breath hold

anaesthaesia

sedation

normal unregulated breathing

gating with free breathingor breath hold

standard fixed delivery

real time tracking

predictive tracking

Slide courtesy of Prof Mike Brada

Questions and Challenges

• How quantitative is functional imaging?• When is IGRT needed?

– High dose treatments without IGRT?• How do methods compare?

– Same/extra information, dose, time, cost?• How good are surrogates?

– Internal markers, external markers• How reproducible is intra-fraction motion?

– Can we measure it sufficiently accurately before irradiation?– Can it be controlled?– Can predict-ahead methods be made to reliably work?

• How does it change our treatment margins and doses and what are consequences for patient?

From Dr Phil Evans



And the press has been interested following David Dearnaley’sinitiative….

Conclusions on IMRT delivery

• In 1988 when inverse planning seriously began there was no 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 isnot 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 Detailed descriptions of both theoretical and both theoretical and

practical IMRT + huge practical IMRT + huge lists of primary lists of primary

references can be found references can be found in these 4 sequential in these 4 sequential

booksbooks

1993 19971997

20002000

20042004


Wednesday 16th June 2010 1

Clinical application of conformal therapy and IMRT

Dr Christopher M Nutting MD FRCP FRCRConsultant and Reader in Clinical Oncology,

Head and Neck Unit, Royal Marsden Hospital & Institute

of Cancer Research, Fulham Road, London

Introduction

• Radiation therapy is a key treatment modality in Head and Neck Cancer

• Primary therapy• Offers cure rates similar to surgery for early disease

• Allows organ preservation and retains function

• Post-operative therapy• Maximises cure rates and permits conservative surgery

Aims of Radiotherapy in Head and Neck Cancer

1. To achieve tumour control by delivering a homogeneous tumouricidal radiation dose to tumour-bearing tissues

2. To avoid radiation-induced complications by minimising dose to normal tissue structures

Pre-radiotherapy assessments I

• Accurate diagnosis– Specialist pathology review of biopsy/FNA

• High concordance for SCC (90%)

• Essential for salivary/lymphoma/early invasion

– Full analysis of post-operative resections• Does the resection confirm the pre-op diagnosis

– Assessment of primary site by EUA/imaging• 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



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 each sub-site and pathology

• Primary tumour– Local spread- mucosal, deep soft tissue, paths of least

resistance, special cases (e.g. ACC)

• Nodal spread– Groups at risk, levels, incidence in N0 and N+

– Lateral vs midline CTV: Unilat or bilat irradiation

– 10-20% risk cut-off usually used for elective irradiation

– Lindberg 1972…..

Local spread of NPC

• 2 routes– Parapharyngeal space

(IX-XII + sympathetic chain)

– Supero-lateral via F. Lacerum to Cav Sinus (II-IV)

Concepts of ICRU applied to HNC

• GTV: demonstrable macroscopic disease from physical findings and imaging– Tumour and enlarged nodes

• CTV: Potential sites of microscopic cancer spread– Around the primary and involved nodes

– Elective neck nodes

• PTV: CTV with a margin for movement and set-up uncertainty

Radiation doses for wide-field irradiation

50Gy 25#Elective nodal groups un-operated

60-66Gy 30-33#Post-operative high risk sites

66-70Gy 33-35#Primary site and involved nodes

Dose conv frac



Accelerated hypo-fractionated UK radiation doses for small volumes

55Gy 20#<6x6cm field size

e.g. T2 N0 glottis

50Gy 16#<5x5cm field size

e.g. T1 N0 glottis

Radiation dose fractionationClinical indication

NB: Manchester Experience of 55Gy in 20 fractions used for locally advanced SCC HN as long as length of irradiated pharynx <8cm

Diagnosis, Staging , Patient factors OK

Tumour CTV

N+ risk >20%

No yes

Local RT to primary site

RT dose based on field size

Radical RT thought pathways for CTV definition

Unilat Bilat

Midline tumour

Levels?Levels?

Post-op Node pos elective

Choose appropriate dose and technique

Radiotherapy techniques I

• Wedged pair techniques for lateralised CTVs– e.g. parotid, oral cavity, early tonsil lesions

• Parallel-opposed lateral fields for midline CTVs– e.g. Larynx, hypopharynx, BOT, nasopharynx

• Anterior/posterior fields for neck irradiation

Wedged pair technique - parotid

• Minimises dose to parotid, spinal cord, oral cavity c/lmucosa and mandible

• Wedges used to improve dose homogeneity

Wedged pair technique – oral cavity

•Suitable for bucmucosa, lateral tongue

•Care with floor of mouth, deeply infiltrative tongue tumours

•Hot spots tend to occur in mandible

Parallel opposed lateral fields

•Optimal for CTVsanterior to spinal cord

•Adverse for mucosal irradiation c.f. Wedged pair technique

•En passant irradiation of adjacent lymph nodes in level 3, probably not clinically relevant



Parallel opposed

lateral fields

Parallel opposed fields for pharyngeal tumours

• Irradiation of mandible, parotid glands, oral cavity, spinal cord

• Always needs modification of fields after ~40-44Gy

Parallel opposed fields for pharyngeal tumours

• 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

Parallel opposed fields for pharyngeal tumours: managing the match line- importance of neck position

Anterior and posterior fields for neck irradiation

IbII

III

IVV

IbII

III

IVV

RPNs



Anterior and posterior fields : be aware of what is under the block!

IbII

III

IVV

Field matching

• Typically lateral fields are used to treat the primary site for mid-line CTVs of the pharynx and larynx

• Bilateral split neck fields are matched below

• 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

Reduced lateral field off cord at40GyMatch electrons to V for a further 10 Gy (total 50 Gy)

•Phase III

15 Gy boost to the larynx PTV using parallel pair.

Practical processes of head and neck radiotherapy

planning



Mould roomMould room

Immobilisation shell Simulation

Treatment planning Radiotherapy planning

•Define field borders

•Outline through centre of volume

•Define treatment volume



Radiotherapy planning

•Anterior and posterior wedged fields

Radiotherapy planning - conventional

•Dose coverage of tumour

•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

• Poor definition of target volume and normal tissues in 3D

• Inability to accurately determine doses to tumour and normal tissues (prognostication)

• Inability to optimise radiotherapy for individual patients to increase dose delivery and minimise risk of complications

Three-Dimensional Conformal Radiotherapy (3DCRT) for Head

and Neck Cancer



CT Planning - Scan Acquisition in Three Dimensions

CT Planning - Tumour Localisation

CT Plan - Planning Target Volume

Movement + uncertainty margin

CT Planning - Volume Definition

CT planning - 3D Reconstruction CT planning - 3D Reconstruction



CT Planning - Beams-Eye-View CT Planning - dose calculation

Volume

of target

Radiation Dose

Normal tissue

Tumour

CT Plan - 3D Plan Evaluation CT Plan - 3D Plan Evaluation

3D Conformal Planning - BenefitsSite Author Benefits

Parotid Nutting 2000 Reduced dose to cochlea by 20%,oral cavity by 30%

Paranasalsinus

Adams 2001 Reduced optic nerve dose by10%, parotid gland dose by 30%,potential to dose escalate

Nasopharynx Zelefsky 1998 Improved parapharyngeal spacecoverage in T2b tumours

Oropharynx Eisbruch 1998 Reduced parotid gland irradiation

Thyroid Nutting 1999 Reduced normal tissue irradiationby40%, spinal cord dose by 50%

Target volume definition in

head and neck cancer



Two components:

1. NODAL OUTLINING

2. PRIMARY TUMOUR OUTLINING

NODAL OUTLINING

Robbins Lymph Node classification :

– Level Ia: submental triangle– 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

Patterns of spread documented in large retrospective surgical series.

Sobotta, 1982

Level

Cranial Caudal Anterior Posterior Lateral Medial

Ia Mandible Hyoid bone Symphysismenti

Body hyoid bone

Ant. Belly of digastric m.

n.a.

Ib Cranial edge SCM

Hyoid bone Symphysismenti; platysma

Post. edge SCM

Mandible, platysma, skin

Lat. edge of ant. belly DG

II Caudal edge lat. process C1

Caudal edge hyoid bone

SM,ICA,post belly DG

Post edge SCM

Medial edge SCM

Med. edge ICA,PS

III Caudal edge hyoid bone

Caudal edge cricoid cart.

Ant edge SCM, postlatedge SH

Post edge of SCM

Medial edge SCM

Med edge ICA,PSm

IV Caudal edge cricoid cart

2cm cranial to SCJ

Ant edge SCM

Post edge of SCM

Medial edge of SCM

Med edge ICA, PS

V Cranial edge hyoid bone

Cervical transverse vessels

Post edge SCM

Ant edge trapezius m

Platysma, skin

PSm

VI Caudal edge thyroid cartilage

Sternalmanubrium

Platysma, skin

Between trachea and oesophagus

Thyroid gl., skin, SCM

n. a.

Gregoire et al 2002

CONSENSUS OUTLINING GUIDELINES Level II – UPPER DEEP CERVICAL

NODES

Anatomy: • From carotid bifurcation

(hyoid) to skull base.• Posterior border of the SCM to

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

Level II: Caudal edge lateral process C1 to caudal edge hyoid bone

Level IIa: post border- ant edge SCM

medial edge IC

A, P

Smmed

ial e

dge

SCM

med

ial e

dge

ICA

, PSm

medial edge SC

M

post edge SCM

SM gland, ICA, post belly Digastric

Level III – MIDDLE JUGULAR NODES

Anatomy:

• 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



Level III: Caudal edge hyoid bone -- caudal edge cricoid cartilage

med

ial e

dge

ICA

, PSm

Ant edge SCM , posterolateral edge Sternohyoid

medial edge SC

M

med

ial e

dge

SCM

post edge SCM

medial edge IC

A, P

Sm

Level IV– LOWER JUGULAR NODES

Anatomy:

• From the junction of the omohyoid muscle with the IJV(cricoid level) to the clavicle.

• Posterior border of the SCM to the lateral border of the sternohyoid muscle

Sobotta, 1982

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

Ant edge SCM m

med

ial e

dge

SCM

post edge SCM

medial edge IC

A, P

Sm

medial edge SC

M

med

ial e

dge

ICA

, PSm

Level V– POSTERIOR TRIANGLE NODES

Boundaries: • Anterior border of the

trapezius muscle to Posterior border of SCM

• Skull base to Clavicle

It includes the supraclavicular nodes

Sobotta, 1982

Level V: Cranial edge hyoid bone to Transverse cervical vessels

Post edge SCM

Platysm

a

Anterior edge trapezius m.

PSm

PSm

Pla

tysm

a


Post edge SCM

Platysm

a

anterior edge trapezius m.

PSm

PSm

Pla

tysm

a




Post edge SCM

anterior edge trapezius muscle

PSm

Pla

tysm

a

PRIMARY TUMOUR OUTLINING

• NO ACCEPTED GUIDELINES

• Sources of information:– Tumour site/ stage

– Tumour natural history

– Anatomical descriptions

– Surgical experience

– Lessons from conventional radiotherapy


• 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

The End!



Implementation Implementation

Helen McNairHelen McNair

Research RadiographerResearch Radiographer

Royal Marsden Foundation Trust Royal Marsden Foundation Trust and Institute of Cancer Researchand Institute of Cancer Research

Technology TimelineTechnology Timeline

CRT

IGRT

VMATIMRT

Electronic Portal Imaging

Port Film

ImprovedImmobilisation

Technology TimelineTechnology Timeline

CRT

IGRT

VMATIMRT

Electronic Portal Imaging

Port Film

ImprovedImmobilisation

How?How?

Site? Patient? Trial?

IMRT ImplementationIMRT Implementation

Site - all patients in that site?

Patient - how can resource it?

Trials - “data on health care and resource use and clinical effectiveness observed in a routine care environment. The new treatment should be compared to the most common existing treatment approach”

Hutton and Maynard, Health Econ 9: 89-93 (2000)

Clinician

Key TeamKey Team

Agree protocols

Maintain Quality

Implement changes

Review process



Teaching

Practical sessions

Dummy rums

TrainingTraining

Higher monitor units

Unable to check - ‘not intuitive’

MLC

Time constraints

Verification

Changes in working practiceChanges in working practice

ImmobilisationImmobilisation

Rethink position

Evaluate accuracy

ReproducibilityReproducibility ReproducibilityReproducibility

Images courtesy of Oncology Imaging systems and Oncology Systems Ltd

“S” typePosicast 4 /5 point fixation

Cantilever board with shoulder depression

Thermoplastic mask systems

4 or 5 fixation points4 or 5 fixation points

Mask shrinkage Mask shrinkage

1.5 1.5 ±± 0.3mm during day 10.3mm during day 1

Maximum 0.5 mm over next 3 daysMaximum 0.5 mm over next 3 days

Tsai et al 1999Tsai et al 1999GilbeauGilbeau et al 2001et al 2001

Thermoplastic shellThermoplastic shell



Thermoplastic shellThermoplastic shell Couch attachment

ReproducibilityReproducibility

Skill of the maker/operatorSkill of the maker/operator

Support systemSupport system

PatientPatient

ReproducibilityReproducibility

97% vectors < 2.5mm

Burton et al, 2002 , Clin Oncol

Stereotactic FrameStereotactic Frame Stereotactic FrameStereotactic Frame

performance statusperformance status

dentitiondentition



Pt changes after makingPt changes after makingshellshell

LimitationsLimitations

Pt changes through Pt changes through course of treatmentcourse of treatment

CT ScanningCT Scanning

Conformal therapy

Levels

Contrast

PlanningPlanning

Outlining1/2 hr Conventional1 1/2 hr IMRT

Dosimetry3 hrs Conventional4.5 hrs IMRT

Allow a week

Head and Neck

SCOR January 2010

TLDs Ion Chamber Film

Delta 4phantom

Time ~ 1.5 hrs

Time ~ 4-5 hrs

VerificationVerification

Courtesy of Liz Miles

Head and Neck

Dosimetry, 5.8

QA, 2.5

Clinician outlining, 2.3

Radiographer, 2.4

Planning ResourcesPlanning Resources Treatment DeliveryTreatment Delivery

IMRT and Conventional treatment times

0

2

4

6

8

10

12

14

16

18

20

single 1 2 3 all phases

IMRT HNC Conventional HNC

Technique

Tim

e (m

ins

)

Data courtesy of Liz Miles



Patient and Fluence VerificationPatient and Fluence Verification

Day 1 Day 14Validation

Orthogonal films, protocols

Films or EPI

Planning issuesPlanning issuesLarge field sizesLarge field sizes

Immobilisation AND reproducibility

Dummy runs

Staff training

Evaluate treatments

ConclusionConclusion



Cross sectional imaging in the Cross sectional imaging in the evaluation and staging of evaluation and staging of

head and neck cancerhead and neck cancer

Julie OlliffJulie OlliffUniversity HospitalUniversity Hospital

BirminghamBirmingham


Learning objectivesLearning objectives Role of imaging in the decision making Role of imaging in the decision making

process of the patient with head and process of the patient with head and neck cancer (laryngeal and pharyngeal neck cancer (laryngeal and pharyngeal cancer)cancer)

ResectableResectable vs. vs. unresectableunresectable Importance of Importance of paraglotticparaglottic and preand pre--

epiglotticepiglottic spacesspaces TransglotticTransglottic spreadspread

Laryngeal cartilage invasionLaryngeal cartilage invasion MetastaticMetastatic diseasedisease

NodalNodal pulmonarypulmonary

Treatment choiceTreatment choice Palliation or cure?Palliation or cure? Medical therapy or surgeryMedical therapy or surgery

ResectableResectable or or unresectableunresectable UnresectableUnresectable does not necessarily does not necessarily

imply incurableimply incurable T4a and T4bT4a and T4b

Vascular encasement and invasionVascular encasement and invasion PrevertebralPrevertebral space invasionspace invasion Invasion of Invasion of mediastinalmediastinal structuresstructures

Radiotherapy or surgery?Radiotherapy or surgery? Early stage T1/2 little evidence to suggest any Early stage T1/2 little evidence to suggest any

advantage between RT and organ preserving advantage between RT and organ preserving surgery (beware anterior com involvement)surgery (beware anterior com involvement)

T3/4 chemoT3/4 chemo--radiation preferredradiation preferred Laryngeal cartilage invasionLaryngeal cartilage invasion

Poor control by radiotherapy with increased risk of Poor control by radiotherapy with increased risk of late complications but studies performed with older late complications but studies performed with older CT scanners. Not necessarily associated with poor CT scanners. Not necessarily associated with poor control.control.

Laryngeal cartilage invasion used to be considered Laryngeal cartilage invasion used to be considered contraindication to RT and partial contraindication to RT and partial laryngectomylaryngectomy

Staging the primary tumourStaging the primary tumour

Mucosal extension better assessed by Mucosal extension better assessed by endoscopyendoscopy

CT/MRI will not detect the majority of CT/MRI will not detect the majority of lesions confined to the mucosa lesions confined to the mucosa

Deep extension is better assessed by cross Deep extension is better assessed by cross sectional imagingsectional imaging

CT/MRI will upstage the primary tumour in CT/MRI will upstage the primary tumour in approx. 25%approx. 25%

How can imaging help the clinicianHow can imaging help the clinician

SubSub--mucosal extensionmucosal extension ParaglotticParaglottic disease volume affects response disease volume affects response

to radiotherapyto radiotherapy Unexpected subUnexpected sub--mucosal extensionmucosal extension

Anterior Anterior commisurecommisure Laryngeal cartilage invasionLaryngeal cartilage invasion T4a and T4bT4a and T4b Unsuspected nodal disease not covered Unsuspected nodal disease not covered

by standard treatmentby standard treatment MetastaticMetastatic spreadspread



ParaglotticParaglottic and preand pre--epiglotticepiglotticspacesspaces

ParaglotticParaglottic Paired fatty regions Paired fatty regions

beneath the true and beneath the true and false cordsfalse cords

Merge superiorly into Merge superiorly into the prethe pre--epiglotticepiglotticspacespace

Laryngeal cartilage invasionLaryngeal cartilage invasion

Ossified cartilage more susceptibleOssified cartilage more susceptible Three phases: inflammatory change within Three phases: inflammatory change within

cartilage adjacent to tumour inducing new cartilage adjacent to tumour inducing new bone formation prior to actual tumour bone formation prior to actual tumour invasion, invasion, osteolysisosteolysis, frank invasion, frank invasion


Diagnostic difficultiesDiagnostic difficulties Variable cartilage ossificationVariable cartilage ossification Tumour itself has similar attenuation values to Tumour itself has similar attenuation values to

nonnon--ossified cartilage but may cause new bone ossified cartilage but may cause new bone formationformation

High signal on MRI may be due to tumour or to High signal on MRI may be due to tumour or to non non neoplasticneoplastic inflammatory changeinflammatory change

Laryngeal cartilage invasionLaryngeal cartilage invasionDiagnostic criteria CT Diagnostic criteria CT –– thyroid (111)thyroid (111) ExtraExtra--laryngeal tumour, sclerosis and erosion or laryngeal tumour, sclerosis and erosion or

lysislysisSensSens 94%, 94%, SpecSpec 38%38%PPVPPV 54%, 54%, NPVNPV 89%89% ExtraExtra--laryngeal tumour and erosion or laryngeal tumour and erosion or lysislysisSensSens 71%, 71%, SpecSpec 83%83%PPVPPV 76%, 76%, NPVNPV 79%79%

Becker et al 1997


Diagnostic criteria CT Diagnostic criteria CT –– all (111)all (111) ExtraExtra--laryngeal tumour and erosion or laryngeal tumour and erosion or

lysislysis, thyroid, , thyroid, arytenoidarytenoid, , cricoidcricoid Sclerosis in the Sclerosis in the cricoidcricoid and and arytenoidarytenoidSensSens 82%, 82%, SpecSpec 79%79%NPVNPV 91%91%

Becker et al 1997

Laryngeal cartilage invasion Laryngeal cartilage invasion --MRIMRI

T2 W hyaline cartilage invaded by T2 W hyaline cartilage invaded by tumour displays a higher SI tumour displays a higher SI

T1W invaded hyaline cartilage and fatty T1W invaded hyaline cartilage and fatty marrow display a low to intermediate marrow display a low to intermediate SI, SI, peritumouralperitumoural inflammatory change inflammatory change may enhance, this is most commonly may enhance, this is most commonly seen in the thyroid cartilage reducing seen in the thyroid cartilage reducing specificity to 56% rather than specificity to 56% rather than cricoidcricoidand and arytenoidarytenoid 87% and 95%87% and 95%

PPV 68PPV 68--71%, NPV 9271%, NPV 92--96%96%Becker M EJR 2000; 33:216-229




T2 weighted or post contrast T1W T2 weighted or post contrast T1W cartilage SI greater than that of adjacent cartilage SI greater than that of adjacent tumour = inflammation, SI similar to that tumour = inflammation, SI similar to that of adjacent tumour = of adjacent tumour = neoplasticneoplastic invasioninvasion

Specificity all 82% (74%), specificity for Specificity all 82% (74%), specificity for thyroid cartilage 75% (54%) thyroid cartilage 75% (54%)

Becker M Radiology 2008; 249:551

Neoplastic invasion


Inflammation of thyroid cartilage


TT--staging of staging of hypopharyngealhypopharyngealcancercancer

T1T1 limited to one limited to one subsitesubsite and <=2cm in and <=2cm in max. dimensionmax. dimension

T2T2 >one >one subsitesubsite or an adjacent or an adjacent subsitesubsite or or measures >2cmsmeasures >2cms

T3T3 >4cms>4cmsT4T4 invades adjacent structures invades adjacent structures eg.thyroideg.thyroid, ,

cricoidcricoid cartilage, carotid artery, soft tissues cartilage, carotid artery, soft tissues of neck, preof neck, pre--vertebral fascia/muscle, vertebral fascia/muscle, thyroid, oesophagusthyroid, oesophagus

Subsites: piriform sinus, post hypoph wall, postcricoid

T staging of T staging of supraglotticsupraglotticcancercancer

T1 T1 tumour limited to one tumour limited to one subsitesubsiteT2T2 invasion of >one adjacent invasion of >one adjacent subsitesubsite of of

supraglottissupraglottis, glottis or region outside of , glottis or region outside of supraglottissupraglottisT3 T3 invasion of post invasion of post cricoidcricoid area, prearea, pre--

epiglottic/paraglotticepiglottic/paraglottic space and/or minor thyroid space and/or minor thyroid cartilage erosioncartilage erosion

T4T4 extraextra--laryngeal spreadlaryngeal spreadT4aT4a through thyroid cartilage or tissues beyond through thyroid cartilage or tissues beyond

eg.Tracheaeg.Trachea, soft tissues of neck, soft tissues of neckT4bT4b prevertebralprevertebral space, space, mediastinummediastinum, carotid, carotid

SubsitesSubsites: mucosa of base of tongue, : mucosa of base of tongue, valleculavallecula, medial wall of , medial wall of pyriformpyriform sinussinus

TT--staging of staging of glotticglottic cancercancer

T1T1 Tumour limited to vocal cordTumour limited to vocal cordT2T2 Extension into supra/sub glottisExtension into supra/sub glottisT3T3 Invasion of Invasion of paraglotticparaglottic spacespace and/or minor and/or minor

thyroid cartilage erosionthyroid cartilage erosionT4T4 ExtralaryngealExtralaryngeal tumour spreadtumour spreadT4aT4a Through thyroid cartilage or tissues beyond Through thyroid cartilage or tissues beyond

larynx larynx egeg. trachea, strap muscles, thyroid. trachea, strap muscles, thyroidT4bT4b prevertebralprevertebral space, space, mediastinummediastinum, , encasement encasement

carotid arterycarotid artery



Radiotherapy or surgery?Radiotherapy or surgery? Limitations in current T staging system re Limitations in current T staging system re

organ conservation therapy or notorgan conservation therapy or not Tumour volumeTumour volume

T1T1--T4 supra T4 supra glotticglottic <= 6ml 83% local control, >6ml <= 6ml 83% local control, >6ml 43% (Mancuso et al 1999)43% (Mancuso et al 1999)

T3 T3 glotticglottic <= 3.5ml 85%local control, >3.5ml 22% <= 3.5ml 85%local control, >3.5ml 22% local control (local control (ParmeijerParmeijer et al 1997)et al 1997)

HypopharyngealHypopharyngeal cancer >6.5ml poor response, also cancer >6.5ml poor response, also tumour >1cm at level of tumour >1cm at level of pyriformpyriform sinus (sinus (ParmeijerParmeijer et et al 1998)al 1998)

High risk profile High risk profile Large tumour volume Large tumour volume Deep tumour spreadDeep tumour spread

ResectabilityResectability issuesissues

Vascular encasementVascular encasement CT overestimatesCT overestimates US with US with transcranialtranscranial Doppler to determine Doppler to determine

crossflowcrossflow MR >270deg. involvement accurate in MR >270deg. involvement accurate in

prediction of inability of surgeon to peel prediction of inability of surgeon to peel tumour off vesseltumour off vessel

PrevertebralPrevertebral fascia involvementfascia involvement

Preservation of fat stripe. Variable width. Preservation of fat stripe. Variable width. Imaging has poor positive predictive valueImaging has poor positive predictive value

Loss of fat stripe, Loss of fat stripe, nodularitynodularity within within prevertebralprevertebral muscle, abnormal T2, abnormal muscle, abnormal T2, abnormal enhancmentenhancment –– even if all four signs are even if all four signs are present 4/7 patients had no present 4/7 patients had no prevertebralprevertebralmuscle infiltration when evaluated at surgery muscle infiltration when evaluated at surgery ((LoevnerLoevner et al 1998) et al 1998)

MediastinalMediastinal invasioninvasion

Little evidenceLittle evidence

Why image neck nodes?Why image neck nodes? Already staging primaryAlready staging primary To identify nodes not clinically To identify nodes not clinically evaluableevaluable ––

retropharyngeal nodes, difficult necksretropharyngeal nodes, difficult necks Surgical decision makingSurgical decision making

Bilateral diseaseBilateral disease ContraContra--lateral diseaselateral disease Nodal sizeNodal size Advanced diseaseAdvanced disease

Vascular encasementVascular encasement Skull base involvementSkull base involvement

To identify bulky nodal disease not treatable by To identify bulky nodal disease not treatable by primary radiotherapyprimary radiotherapy

Pulmonary metastasesPulmonary metastases

Lung metastases is the most common site Lung metastases is the most common site of distant metastases in head and neck SCCof distant metastases in head and neck SCC

The management of isolated nonThe management of isolated non--significant lung nodules (defined as significant lung nodules (defined as subcentimetresubcentimetre nodules) is been much nodules) is been much debated, with PET scanning, computer debated, with PET scanning, computer aided diagnosis and video assisted aided diagnosis and video assisted thoracoscopythoracoscopy (VATS) being suggested to (VATS) being suggested to guide diagnosisguide diagnosis



Lung nodules (unlikely to represent Lung nodules (unlikely to represent metastases) are common in head and metastases) are common in head and neck neck sccscc (14.6%)(14.6%)

12% of these developed lung cancer12% of these developed lung cancer Options for management of these Options for management of these

nodules include repeat CT scan at 6nodules include repeat CT scan at 6--12 12 months to assess for progression, PET months to assess for progression, PET scan or biopsy (either scan or biopsy (either radiologicallyradiologically or or by VATS)by VATS)

Conclusion Conclusion Role of imagingRole of imaging ParaglotticParaglottic spreadspread

Volume Volume Extent Extent

Laryngeal cartilage invasionLaryngeal cartilage invasion ExtraExtra--laryngeal extensionlaryngeal extension Nodal and pulmonary statusNodal and pulmonary status

Unilateral / bilateral, volume, adverse featuresUnilateral / bilateral, volume, adverse features Significant pulmonary noduleSignificant pulmonary nodule

497 CT scans reviewed497 CT scans reviewed 187 with head and neck 187 with head and neck sccscc

16 excluded (11 duplicates and 5 had no notes 16 excluded (11 duplicates and 5 had no notes available)available)

25 patients with non25 patients with non--significant lung nodules significant lung nodules 3 of these malignant3 of these malignant

27 patients with significant lung nodules27 patients with significant lung nodules 24 malignant24 malignant

3 patients with a normal CT scan on screening 3 patients with a normal CT scan on screening developed lung cancer at later datedeveloped lung cancer at later date

Day 1 Session 2 Lecture 512:30pm


IMRT treatment planning IMRT treatment planning basicsbasics

Dr Catharine Clark

Steps in InverseSteps in Inverse--planned IMRTplanned IMRT

1.1. Define clinical dose specificationsDefine clinical dose specifications2.2. Delineate contoursDelineate contours3.3. Select Select isocentreisocentre and beam orientationand beam orientation4.4. Define optimisation parameters and Define optimisation parameters and

priority factorspriority factors5.5. Optimise planOptimise plan6.6. Convert Convert fluencesfluences to leaf motionsto leaf motions7.7. CalculateCalculate8.8. AnalysisAnalysis

Define clinical dose specificationsDefine clinical dose specifications

Dose prescriptionDose prescription Primary target dose and fractionationPrimary target dose and fractionation Secondary (elective target) dose and Secondary (elective target) dose and

fractionatationfractionatation Decide what these doses are prescribed toDecide what these doses are prescribed to

–– IsocentreIsocentre–– VolumeVolume–– IsodoseIsodose lineline

Dose constraintsDose constraints Organs at RiskOrgans at Risk

–– Spinal cord, brainstemSpinal cord, brainstem–– Parotid glandsParotid glands

Volumes of interestVolumes of interest–– Larynx regionLarynx region–– Oral cavityOral cavity


Targets have a minimum and maximum dose value.

a specification of the acceptable doses to be delivered to or avoided by those volumes

OARs have a maximum allowed dose and sometimes other volume/dose limits


Including all volumes of (any) interest

full 3D outlining of the volumes

Delineate contoursDelineate contours



Selecting beam parametersSelecting beam parameters

IsocentreIsocentre positionposition–– Can affect field splitting and Can affect field splitting and MUsMUs

How many beams?How many beams? Beam directions?Beam directions?

•• equispacedequispaced??•• nonnon--coplanar?coplanar?•• need to consider setneed to consider set--up limitationsup limitations

Collimator angles?Collimator angles?•• may need to consider MLC limitationsmay need to consider MLC limitations

MLCsMLCs have physical limitations e.g.have physical limitations e.g.–– Minimum leaf separationMinimum leaf separation–– Maximum overMaximum over--traveltravel

These need to be accounted for by the TPSThese need to be accounted for by the TPS

Selection of planning parameters may Selection of planning parameters may minimise problemsminimise problems–– Gantry angleGantry angle–– Collimator angleCollimator angle–– IsocentreIsocentre positionposition


• Equispaced fields may not be the most practical• Avoid treating through unnecessary tissue• Need to consider potential collisions and avoid beams passing through the couch and immobilisation systems• Adjust gantry and collimator rotations• Small adjustments not so critical to plan result as can often be taken into account by fluence


3 different dose-volume sets

1. Clinicians goals2. Planning parameters3. Final dose distribution

Need to know how to interpret one into another

Optimisation parametersOptimisation parameters

Planner describes problem

Planner changes how he describes problem

Planning system develops plan

Evaluate plan

Unacceptable Acceptable

FINISH !!


Avoid conflicting requestsAvoid conflicting requests–– Where structures overlap, decide Where structures overlap, decide

beforehand what beforehand what youyou want the want the compromise to becompromise to be

–– DonDon’’t ask for dose in impossible places t ask for dose in impossible places (e.g. build(e.g. build--up region)up region)

–– Be realisticBe realistic




May need to set tighter constraints than May need to set tighter constraints than actually requiredactually required

System allows interaction with constraints as System allows interaction with constraints as optimisation proceedsoptimisation proceeds–– can start with relaxed constraints and tighten as can start with relaxed constraints and tighten as

necessarynecessary

Beware of unattainable constraints, e.g.Beware of unattainable constraints, e.g.–– maximum dose of 40Gy in an OAR which overlaps maximum dose of 40Gy in an OAR which overlaps

a PTV with a minimum dose of 60Gya PTV with a minimum dose of 60Gy–– high dose required in buildhigh dose required in build--up regionup region

Optimisation parametersOptimisation parameters OptimiseOptimise the planthe plan

Optimisation and deliveryOptimisation and delivery

Planner describes problem

Planner changes how he describes problem

Planning system develops plan

Evaluate plan

Unacceptable Acceptable

FINISH !!

Generate deliverable plan

Evaluate plan

Make adjustments

Unacceptable

Acceptable

Delivery considerationsDelivery considerations

Delivery sequence generated after Delivery sequence generated after optimisationoptimisation

How the How the fluencefluence is actually delivered will is actually delivered will affect the dose distributionaffect the dose distribution–– head scatterhead scatter–– transmission / leakagetransmission / leakage–– (tongue(tongue--andand--groove)groove)

Conversion optionsConversion options Plan normalisationPlan normalisation

IMRT plans may not have the IMRT plans may not have the isocentreisocentrein an appropriate position for in an appropriate position for normalisationnormalisation

IMRT plans may have nonIMRT plans may have non--uniform dose uniform dose across the target => normalisation across the target => normalisation point may be in slightly hot/cold regionpoint may be in slightly hot/cold region

Often better to normalise to the mean Often better to normalise to the mean or median target doseor median target dose



Class solutionsClass solutions

Determined from planning studies of a Determined from planning studies of a group of patientsgroup of patients

Give a set of starting parameters for the Give a set of starting parameters for the optimisation, which will generally meet optimisation, which will generally meet the plan requirementsthe plan requirements

Class solutionsClass solutions

no. of beamsno. of beams–– e.g. 5 or 7e.g. 5 or 7

beam energybeam energy–– e.g. 6MVe.g. 6MV

beam directions & collimator anglesbeam directions & collimator angles–– e.g. e.g. equispacedequispaced or set anglesor set angles

starting dosestarting dose--volume constraintsvolume constraints

Example: H&N IMRT planExample: H&N IMRT plan

Difficult to deliver radical radiotherapy due to Difficult to deliver radical radiotherapy due to complex anatomy; spinal cord (which is complex anatomy; spinal cord (which is susceptible to radiation damage) sits within susceptible to radiation damage) sits within concavity in target volumeconcavity in target volume

Clinical trial of IMRT Clinical trial of IMRT commenced: commenced: •• PTV1 receives 65Gy in 30 #PTV1 receives 65Gy in 30 #•• PTV2 receives 54Gy in 30 #PTV2 receives 54Gy in 30 #

5 field class solution5 field class solution

Anterior (0°)

RPO (240°)

RAO (300°)

LAO (60°)

LPO (120°)

Initial dose constraintsInitial dose constraints

Planning DVH points are set for each of the organs.

OARs have a minimum dose of 0Gy and a maximum allowed dose

Targets have a minimum and maximum dose value.

Optimisation stops when maximum number of iterations reached or user chooses to stop

User works with the constraints and priorities to guide the system towards the optimal solution



Leaf Motion CalculatorLeaf Motion CalculatorThe conversion of the ‘optimal’ fluence to the‘actual’fluence takes into account the characteristics of the MLCs

• Transmission• Rounded shape of leaf ends• Dose rate

• Available leaf speeds• Maximum field width

5 field class solution5 field class solutionAnterior (0°)

RPO (240°)

RAO (300°)

LAO (60°)

LPO (120°)

Dose distributionsDose distributions

95% isodose 78.9% isodose

DVH calculated from actual DVH calculated from actual fluencesfluences

PTV normalised to 50% volat 65 Gy

SummarySummary

It is important to perform planning studies It is important to perform planning studies prior to clinical implementationprior to clinical implementation•• demonstration of expected benefitsdemonstration of expected benefits•• familiarisation with planning methodsfamiliarisation with planning methods•• assessment of practicalityassessment of practicality•• development of development of ‘‘class solutionsclass solutions’’•• establish clinical trial protocolsestablish clinical trial protocols

Day 1 Session 3 Practical Session2:00pm


The The parapharyngealparapharyngeal spacespace


Birmingham Birmingham UKUK


What is the What is the parapharyngealparapharyngeal spacespace

Central fat filled spaces in lateral supraCentral fat filled spaces in lateral supra--hyoid hyoid neck with important spaces around themneck with important spaces around them

ContentsContents Fat, minor salivary glands, internal maxillary artery, Fat, minor salivary glands, internal maxillary artery,

ascending pharyngeal artery, ascending pharyngeal artery, pterygoidpterygoid venous plexusvenous plexus Surrounding spacesSurrounding spaces

Pharyngeal mucosal space, masticator space, parotid Pharyngeal mucosal space, masticator space, parotid space, carotid space, lateral retropharyngeal spacespace, carotid space, lateral retropharyngeal space

No fascia separates inferior PPS from posterior No fascia separates inferior PPS from posterior submandibularsubmandibular space space

What are the What are the parapharyngealparapharyngealspaces?spaces?

Masticatorspace

Parapharyngealspace

Carotidspace

PharyngealMucosal space

Parotidspace

Central fat filled spaces in lateral supraCentral fat filled spaces in lateral supra--hyoid neck with hyoid neck with important spaces around themimportant spaces around them

AnatomyAnatomy

How to imageHow to image

MRI generally preferred for supraMRI generally preferred for supra--hyoid hyoid neckneck

Axial T1SE Axial T1SE –– good for anatomy and flow good for anatomy and flow voidsvoids

Axial T2 SE, STIR Axial T2 SE, STIR –– good for morphologygood for morphology Post contrast T1 Post contrast T1 –– enhancement enhancement

characteristics (care over timing)characteristics (care over timing) CT for skull base involvementCT for skull base involvement

How to reportHow to report

Determine anatomical site of origin using pattern Determine anatomical site of origin using pattern of displacement of PPS fat and position of of displacement of PPS fat and position of internal carotid artery internal carotid artery –– remember most lesions remember most lesions of PPS arise from adjacent supraof PPS arise from adjacent supra--hyoid neck hyoid neck spacesspaces

Remember anatomical contents of each space to Remember anatomical contents of each space to form differential diagnosisform differential diagnosis

Narrow differential diagnosisNarrow differential diagnosis Clinical historyClinical history Morphology Morphology egeg. Pattern of contrast . Pattern of contrast enhancmentenhancment Frequency of conditionFrequency of condition



Anatomy Anatomy –– parotid spaceparotid space Mass Mass –– parotid spaceparotid space

PleomorphicPleomorphicadenomaadenoma

WarthinWarthin tumourtumour MucoepidermoidMucoepidermoid AdenocysticAdenocystic CaCa Metastasis Metastasis ––SCC, SCC,

melanomamelanoma BranchogenicBranchogenic

anomalyanomaly

Parotid spaceParotid space-- stylostylo--mandibularmandibulartunneltunnel

Anatomy Anatomy –– masticator spacemasticator space

Mass Mass -- masticator spacemasticator space OdontogenicOdontogenic

abscessabscess Malignant Malignant

tumour tumour –– NHL, NHL, sarcoma, SCC sarcoma, SCC from from retromolarretromolartrigonetrigone, , rhabdomyosarcorhabdomyosarcomama (paediatric)(paediatric)

Carotid spaceCarotid space



Mass Mass -- Carotid spaceCarotid space IJV thrombosisIJV thrombosis ICA thrombosis, ICA thrombosis,

dissection, dissection, aneurysm etc.aneurysm etc.

Paraganglioma:gloParaganglioma:glomusmus jugularejugulare, , vagalevagale, carotid , carotid body tumourbody tumour

Nerve sheath Nerve sheath tumour: tumour: schwannomaschwannoma

Lymph node metLymph node met

Lateral retropharyngeal spaceLateral retropharyngeal space

Lateral retropharyngeal spaceLateral retropharyngeal space LymphadenopathyLymphadenopathy

reactivereactive, , inflaminflam, , suppurativesuppurative, , malignant (SCC, malignant (SCC, NHL, NHL, melanoma, melanoma, thyroidthyroid))

Direct invasion Direct invasion from primary SCC from primary SCC esp. posterior wallesp. posterior wall

Pharyngeal mucosal spacePharyngeal mucosal space Adenoidal/Adenoidal/tonsillartonsillar

inflammation, inflammation, abscessabscess

Juvenile Juvenile angiofibromaangiofibroma

SCCSCC NHLNHL

Position of ICAPosition of ICA

Parotid and extraParotid and extra--parotid salivary gland parotid salivary gland tumours displace ICA tumours displace ICA posteriorlyposteriorly

ParagangliomasParagangliomas and most and most schwannomasschwannomasdisplace ICA displace ICA anteriorlyanteriorly

True lesions of True lesions of parapharyngealparapharyngeal fat fat spacespace

Salivary gland tumoursSalivary gland tumours Parotid gland migrates Parotid gland migrates embryologicallyembryologically from from

pharyngeal wall and may leave pharyngeal wall and may leave ectopicectopicsalivary tissue in salivary tissue in parapharyngealparapharyngeal space space

NeurogenicNeurogenic tumours tumours –– schwannomaschwannoma from from sympathetic chain (rare)sympathetic chain (rare)



Non visualisation fat between mass Non visualisation fat between mass and parotidand parotid

Tumour of parotid origin (80%)Tumour of parotid origin (80%) Large extraLarge extra--parotid tumourparotid tumour Tumour adherent to parotid capsuleTumour adherent to parotid capsule Tumour invasive (rare)Tumour invasive (rare)

SchwannomaSchwannoma vsvs paragangliomaparaganglioma

ParagangliomaParaganglioma -- high velocity flow voids on high velocity flow voids on unenhancedunenhanced T1scansT1scans

ParagangliomaParaganglioma -- hypervascularhypervascular on early phase on early phase with wash outwith wash out

Carotid body Carotid body paragangliomaparaganglioma may splay ICA/ECAmay splay ICA/ECA SchwannomaSchwannoma hypovascularhypovascular but may show but may show

enhancement on delayed scans post IV contrastenhancement on delayed scans post IV contrast Involvement of skull baseInvolvement of skull base

SchwannomasSchwannomas ––smooth and well definedsmooth and well defined ParagangliomasParagangliomas –– shaggy appearing marginsshaggy appearing margins

Infection Infection

Most arise in other spaces and extend into Most arise in other spaces and extend into parapharyngealparapharyngeal space space –– odontogenicodontogenic, , pharyngeal, pharyngeal, otogenicotogenic

ComplicationsComplications IJV thrombosisIJV thrombosis Carotid artery aneurysm and ruptureCarotid artery aneurysm and rupture MediastinitisMediastinitis Meningitis Meningitis

Conclusion Conclusion

Look for the position of the fatLook for the position of the fat Look for the position of the ICALook for the position of the ICA Morphology of massMorphology of mass Remember the contents of the spaces and Remember the contents of the spaces and

the common pathologiesthe common pathologies



Romania 2010

PET/CT in lung & oesophageal cancerSheila RankinGuy’s & St Thomas’London UK

Functional imagingFunctional imaging AdvantagesAdvantages Identifies metabolically active tissueIdentifies metabolically active tissue Depends on activity not sizeDepends on activity not size Whole body imaging techniqueWhole body imaging technique Assess treatment response prior to size Assess treatment response prior to size

changechange Post treatment anatomic distortion less Post treatment anatomic distortion less

significantsignificant Quantitative measurements Quantitative measurements –– SUVSUV

SUV = SUV = FDGFDGregionregion/FDG/FDGdosedose Body WtBody Wt

PET/CT in lung PET/CT in lung cancercancer

Lung CancerLung Cancer>380,000 new cases/year in EU>380,000 new cases/year in EUCommonest cause of cancer deathCommonest cause of cancer death80% NSCLC80% NSCLCPoor overall survivalPoor overall survival 1 year survival1 year survival 25%25% 5 year survival5 year survival 7 7 -- 15% 15% Stage 1 60Stage 1 60--80%80% Stage 1V 1.6 Stage 1V 1.6 --2%2% 2020--30% eligible for surgery30% eligible for surgery

FDGFDG--PET in nodules T1PET in nodules T1

SUV > 2.5SUV > 2.5

Sensitivity 94%Sensitivity 94%

Specificity 71%Specificity 71%

Accuracy 86%Accuracy 86%

PPV 90%PPV 90%

NPV 85%NPV 85%

False positives

Granulomas

Abscess

Sarcoid

Amyloid

Wegener’s

Rheumatoid

Histoplasmosis

Aspergillosis



False negatives

Bronchoalveolar cell carcinoma

Carcinoid

Tumours < 1cm

FDG PET in T1 tumoursFDG PET in T1 tumours

FDG PET FDG PET vsvs CT nodules < 3cmCT nodules < 3cm 136 nodules 81 malignant 55 benign136 nodules 81 malignant 55 benign <1cm all negative on PET (8<1cm all negative on PET (8--M, 12M, 12--B)B) 11--3 cm 15 FN, 15 FP (733 cm 15 FN, 15 FP (73--M, 43M, 43--B)B) Sensitivity 79%, specificity 65%Sensitivity 79%, specificity 65% Solid nodules Solid nodules senssens 90%, spec 71%90%, spec 71% Ground glass Ground glass senssens 10%, spec 20%10%, spec 20%

NomoriNomori Lung Cancer 2004:45Lung Cancer 2004:45

T definitions T definitions -- T3T3Tumour any size that Tumour any size that

invadesinvades Chest wall (superior Chest wall (superior

sulcus)sulcus) DiaphragmDiaphragm Mediastinal pleuraMediastinal pleura Parietal pericardiumParietal pericardium Tumour < 2cm from Tumour < 2cm from

carinacarina Nodules in same lobeNodules in same lobe Tumours > 7cmTumours > 7cm

T definitions T definitions –– T4T4Tumour any size that Tumour any size that

invadesinvades Mediastinum Mediastinum Heart, great vesselsHeart, great vessels Carina, trachea, Carina, trachea,

oesophagusoesophagus Vertebral bodyVertebral body

Nodules in different Nodules in different lobe, ipsilateral lunglobe, ipsilateral lung PET/CT more accurate than CE CT for T PET/CT more accurate than CE CT for T

stage 86% stage 86% vsvs 79%79%Shim Radiology 2005Shim Radiology 2005



Prognosis Prognosis Lung cancerLung cancer

SUV <5.5 14% recurSUV <5.5 14% recur SUV > 5.5 37% recur SUV > 5.5 37% recur

GoodgameGoodgame J Thor Onc 2008J Thor Onc 2008

SUV < 9 2 year survival 96%SUV < 9 2 year survival 96% SUV > 9 2 year survival 68%SUV > 9 2 year survival 68%

Downey JCO 2006Downey JCO 2006

SUV > 20 median survival < 6 monthsSUV > 20 median survival < 6 months DhitalDhital 20002000

SUV SUV -- prognosisprognosis

Davies A et al Lung Cancer 2007

N1 – nodes removable at pneumonectomy/lobectomy

False Positives

TB Histoplasmosis

Sarcoid COPD

Anthracosis

PET and CT similar

Ebihara Jpn JCO 2006

N2 – ipsilateral mediastinal &subcarinal nodes

N3 – contralateral/supraclavicular nodes

SUV 2.5 often used

SUV 5.3 Accuracy for malignancy 92%

Bryant Ann Thorac Surg 2006



80%80%70%70%60%60%5050de de WeverWever20072007

85%85%70%70%122122YangYang20082008

74%74%78%78%170170MalekMalek20082008

78%78%

93%93%

76%76%

56%56%

68%68%400400

129129

CerfolioCerfolio20032003

CerfolioCerfolio20042004

Use SUV 5.3Use SUV 5.3

PET/CTPET/CTPETPETCTCTNo:No:AuthorAuthor

N Stage - accuracy

Cost effectiveness of Cost effectiveness of mediastinsocopymediastinsocopy

Clinical Stage 1 (CT and PET)Clinical Stage 1 (CT and PET) Unsuspected N2 disease in 5.9%Unsuspected N2 disease in 5.9% Benign nodules 8%Benign nodules 8% Mediastinoscopy added 0.008 years life Mediastinoscopy added 0.008 years life

expectancyexpectancy Cost $250,989 per lifeCost $250,989 per life--year gainedyear gained If prevalence of N2 disease >10%If prevalence of N2 disease >10% Cost $100,000 per lifeCost $100,000 per life--year gainedyear gained

Meyers J Meyers J ThoracThorac CardiovascCardiovasc SurgSurg 20062006

Nodal stagingNodal staging

PET/CT PET/CT EUS EUS MediastinoscopyMediastinoscopyNN00 NN2 2 in 3.7%in 3.7% NN2 2 in 2.9%in 2.9%NN11 NN22 in 23.5%in 23.5% NN2 2 in 17.6%in 17.6%If NIf N00 on PET, occult Non PET, occult N2 2 more likely ifmore likely if

SUV > 10, Adenocarcinoma, RUL (10% N2)SUV > 10, Adenocarcinoma, RUL (10% N2)Mediastinoscopy in this group or N1, not N0Mediastinoscopy in this group or N1, not N0

CerfolioCerfolio Chest 2006Chest 2006

PET/CT EBUS

N0 N2 in 6%

Herth Chest 2008

FDG FDG -- PET in Lung cancerPET in Lung cancer

Distant metastases are common in up to 20% Distant metastases are common in up to 20% of patientsof patients

100 patients unsuspected metastases100 patients unsuspected metastases6 (9%) of 69 with N0/N1 disease6 (9%) of 69 with N0/N1 disease7 (28%) of 25 with N2 disease7 (28%) of 25 with N2 disease6 (100%) of 6 with N3 disease6 (100%) of 6 with N3 diseaseNo false positivesNo false positives

WederWeder. Ann Thoracic Surg.1998.66:886. Ann Thoracic Surg.1998.66:886

PPV 98% if both +ve

PPV 61% if PET +veonly

PPV 17% if PET -ve



Staging of NSCLCStaging of NSCLCCTCT PETPET PET/CTPET/CT

TumourTumour 68%68% 46%46% 86%86%NodesNodes 66%66% 70%70% 80%80%MetastasesMetastases 88%88% 96%96% 98%98%TNMTNM 46%46% 30%30% 70%70%OverstageOverstage TT 20%20% 16%16% 8%8%UnderstageUnderstage TT 12%12% 38%38% 6%6%OverstageOverstage NN 28%28% 20%20% 16%16%UnderstageUnderstage NN 6%6% 10%10% 4%4%

De De WeverWever EurEur RadiolRadiol 20062006

FDGFDG--PET in restaging after PET in restaging after induction therapyinduction therapy

54 patients post CRT54 patients post CRT

PrimaryPrimary NodesNodes

SensitivitySensitivity 94.5%94.5% 77%77%

SpecificitySpecificity 80%80% 68%68%

AccuracyAccuracy 91%91% 73%73%

Negative PET (SUV < 2.5) or SUV >80% Negative PET (SUV < 2.5) or SUV >80% predict a favourable outcome, if <25% 5yr predict a favourable outcome, if <25% 5yr survival 5%survival 5%

EschmannEschmann EurEur J J NucNuc Med Mol Med Mol ImagImag 20072007

Restaging N2 diseaseRestaging N2 disease

Limitations

Nodes FP 25%

FN 20%

Bx if still metabolically activeCerfolio. J Thorac & Cardio Surgery 2006

CT 60%

PET-CT 83%

Mediastinoscopy 60%

(sensitivity 29%)De Leyn J Clin Onc 2006

Recurrence following surgeryRecurrence following surgery Recurrence rate 37.5 Recurrence rate 37.5 -- 50%50% 90% within 2 years90% within 2 years LocoLoco--regionalregional 23 23 -- 40%40% DistantDistant 66 66 -- 74%74% LocoLoco--regional+Distantregional+Distant 9.5 9.5 -- 14%14% Overall Overall AdenoCaAdenoCa > SCC> SCC PneumonectomyPneumonectomy 54%, 54%, lobectomylobectomy 34%34%

Jang. J Thor Jang. J Thor ImagImag 20032003

Walsh Ann Thor Walsh Ann Thor SurgSurg 19951995

Bronchial stump recurrence 15-44%

Wedge > radical surgery (79% vs34%)



2005 2007

Role of PET/CT in Lung CancerRole of PET/CT in Lung Cancer

ConclusionsConclusions Use in patients with stage 1 or 11 disease to Use in patients with stage 1 or 11 disease to

further stage the patient prior to surgeryfurther stage the patient prior to surgery

Use prior to radical radiotherapy and for RT Use prior to radical radiotherapy and for RT planningplanning

Use for minimal N2 disease if surgery an optionUse for minimal N2 disease if surgery an option

Assessment post induction chemoAssessment post induction chemo--RTRT

Suspected recurrent diseaseSuspected recurrent disease

PET/CT in PET/CT in Oesophageal cancerOesophageal cancer

Dr S C RankinDr S C Rankin

GuyGuy’’s & St Thomass & St Thomas’’ Foundation Trust, Foundation Trust, LondonLondon

Oesophageal cancerOesophageal cancerSCCSCC

Associated head & neck cancer, smoking, Associated head & neck cancer, smoking, alcohol, HPV, alcohol, HPV, achalasiaachalasia

Male, lower socioMale, lower socio--economic groupeconomic group

mid oesophagus (75%)mid oesophagus (75%)

AdenocarcinomaAdenocarcinoma

BarrettsBarretts, G, G--O refluxO reflux

Male, upper socioMale, upper socio--economic groupeconomic group

Distal third (94%)Distal third (94%)

Oesophageal cancerOesophageal cancerIncidenceIncidenceSCCSCC 55--10/100,00 in west. 100/100,000 in east10/100,00 in west. 100/100,000 in eastAdenocarcinomaAdenocarcinoma commoner in west than SCC. 5commoner in west than SCC. 5--12/100,000. 12/100,000.

Increased 400Increased 400--800% since 1970800% since 1970PrognosisPrognosis Tumour lethality rate of 0.95Tumour lethality rate of 0.95 If operable 5If operable 5--20% survival20% survival Most inoperable treated with Most inoperable treated with chemoRTchemoRT



Primary Tumour (T)T0 No evidence of primary tumourTis Carcinoma in situT1 Tumour confined to mucosa or invades lamina propria or submucosaT2 Tumour invades muscularis propriaT3 Tumour invades adventitiaT4 Tumour invades adjacent structures

Benign uptake in oesophagitis

Sensitivity for primary 63-95%

High in SCC

Low uptake in 20% of adenoCa

• diffuse

• poorly differentiated

• mucus containing tumours

T Stage

T1

PET/CT in differentiation benign PET/CT in differentiation benign from malignant lesionsfrom malignant lesions

MalignantMalignant Eccentricity (Eccentricity (TisTis, T1, T2), T1, T2) Focal (Focal (TisTis, T1, T2), T1, T2)

Sensitivity 83.3%, specificity Sensitivity 83.3%, specificity 68.2% for malignancy 68.2% for malignancy SUV > 3 (only useful in T2, not T1 SUV > 3 (only useful in T2, not T1 and and TisTis) in differentiation from benign ) in differentiation from benign

lesionslesions

RoedlRoedl. AJR 2008. AJR 2008

T2 eccentric

N stage

N stageSensitivity 51%

Specificity 84%

False negative

• Small nodes

• Close to primary

False positives

• Inflammation

• Anthracosis

• SarcoidVan Westreenen J CO 2006

M stage – FDG-PET

Accuracy 72-88%

Liberale 2004 EJSO

Sihvo 2004 J Gastrointest Surg



Prognosis Prognosis –– oesophageal canceroesophageal cancerLow survival timeLow survival time Positive nodes on FDGPositive nodes on FDG--

PET pre chemoPET pre chemo Number of positive nodesNumber of positive nodes Tumour length on FDGTumour length on FDG--

PETPET SUV. Higher the SUV SUV. Higher the SUV ––

poorly differentiated poorly differentiated tumours tumours

4 year survival SUV < 6.6 4 year survival SUV < 6.6 89%, > 6.6 31%89%, > 6.6 31%

CerfolioCerfolio Ann Thor Ann Thor SugSug 20062006

NeoadjuventNeoadjuvent chemotherapychemotherapy

Chemotherapy + surgeryChemotherapy + surgery Complete resection in 60%Complete resection in 60% Median survival 16.8 monthsMedian survival 16.8 months 2 year survival 43%2 year survival 43%Surgery onlySurgery only Complete resection 54%Complete resection 54% Median survival 13.3%Median survival 13.3% 2 year survival 34%2 year survival 34%

MRC OEMRC OE--02 (2002) 02 (2002)

Oesophageal cancerOesophageal cancer Locally advanced diseaseLocally advanced disease

Median survival 3Median survival 3--5 months5 months

5 year survival following resection 105 year survival following resection 10--35%35%

ChemoChemo--radiotherapy usedradiotherapy used

To downstage tumourTo downstage tumour

Improve complete resection rateImprove complete resection rate

Improve 3 year survivalImprove 3 year survival

Eradicate microscopic metastasesEradicate microscopic metastases

Reduce Reduce locoregionallocoregional recurrencerecurrenceUrschelUrschel Am J Am J SurgSurg 20032003

NeoNeo--adjuventadjuvent chemoRTchemoRT

1515--19% non responders or progress19% non responders or progress No benefit from therapyNo benefit from therapy

ToxicityToxicity

Surgical delays so inappropriateSurgical delays so inappropriate

Survival worse than patients who undergo Survival worse than patients who undergo surgery alonesurgery alone

Greater post op morbidity/mortalityGreater post op morbidity/mortality

Change of therapyChange of therapy

Response assessmentResponse assessment

EarlyEarly

After 1 week of induction therapy After 1 week of induction therapy

to assess responsivenessto assess responsiveness

LateLate

After completion of induction therapy toAfter completion of induction therapy to

assess residual disease and provideassess residual disease and provide

prognostic informationprognostic information

Responder

Chak. Cancer 2000

Using a reduction of > 50% in maximal cross sectional area

Sensitivity 87%

PPV 80%

Non responder



pre

post

-10% -30%Beer Radiology 2006

Volumetric method

2 weeks after chemotherapy

Reduction of 14.8%

Predict histologic response with 100% sensitivity, 53% specificity

No correlation between tumour reduction and progression free survival

PET/CT in response to therapyPET/CT in response to therapy

Change in metabolic activity precedes Change in metabolic activity precedes

anatomic changeanatomic change

Early response on PETEarly response on PET

14 days post chemotherapy14 days post chemotherapy SUV reduction of 35%SUV reduction of 35% Responders more chemo then surgery, Responders more chemo then surgery, Non Responders surgeryNon Responders surgery Follow up median 2.3 yearsFollow up median 2.3 years

Path Path RespResp median overall survivalmedian overall survival EFSEFS(<10% cells)(<10% cells)

RespondersResponders 58%58% not reachednot reached 29/1229/12Non respondersNon responders 0%0% 25/12 25/12 14/1214/12

MUNICON trial Lancet MUNICON trial Lancet OncolOncol 20072007

FDG at 14 days and completion of therapy

No correlation at 14 days between decreased FDG uptake and tumour size on CT, did correlate at end of therapy

Change in activity at 14 days more specific for response that at completion of therapy

Wieder J Nuc Med 2005

Wieder JCO 2004

Response to therapyResponse to therapyCriteria for non respondersCriteria for non responders CT wall thickness > 14.5 mmCT wall thickness > 14.5 mm EUS tumour length > 1cmEUS tumour length > 1cm PET SUV > 4PET SUV > 4

PET CT EUS

Accuracy 76% 62% 68%

None can differentiate complete response from microscopic (<10% cells) disease

Only SUV > 4 independent predictor of survival (2 yr survival 34 vs 64%)

Swisher Ann Thor Surg 2004

ReRe--staging post chemo/RTstaging post chemo/RT

AccuracyAccuracy T4 vsT1T4 vsT1--33 NodesNodes

CTCT 76%76% 78%78%EUS/FNAEUS/FNA 80%80% 78%78%FDGFDG--PET/CTPET/CT 80%80% 93%93%

Complete Response accuracyComplete Response accuracyCTCT 71%71%EUSEUS 67%67%FDGFDG--PET/CTPET/CT 89%89%

Cerfolio 2005 J Thorac Cardiovasc Surgery



Recurrent diseaseRecurrent disease Recurrence rateRecurrence rate 3434--79%79% Higher initial T and N stageHigher initial T and N stage 50% in first year, most within 2 years50% in first year, most within 2 years 30% in operative field30% in operative fieldPM study PM study 63% had disease following curative surgery63% had disease following curative surgery 43% who died from other causes had 43% who died from other causes had

recurrent diseaserecurrent disease

Sites of recurrenceSites of recurrence

LocoregionalLocoregional-- Mediastinal nodes, Mediastinal nodes, anastomosisanastomosis

DistantDistant Abdominal nodesAbdominal nodes

LungLung

LiverLiver

PleuraPleura

AdrenalAdrenal

Sites of recurrenceSites of recurrence

Less commonLess common –– cervical nodes, cervical nodes,

peritoneum, boneperitoneum, bone

EUS/CTEUS/CT PETPET

SensitivitySensitivity 89%89% 96%96%

SpecificitySpecificity 79%79% 68%68%

AccuracyAccuracy 84%84% 82%82%

ConclusionConclusion FDGFDG--PET provides more information PET provides more information

about response to therapy and prognosisabout response to therapy and prognosis

PET and CT similar for recurrent diseasePET and CT similar for recurrent disease

Use FDGUse FDG--PET for problem solvingPET for problem solving

Surgical distortionSurgical distortion

Rising markersRising markers



Interfaces Between Classical and Molecular Radiobiology

Dr Kevin Harrington PhD FRCP FRCR

Reader in Biological Cancer Therapies

Cochrane Shanks/Jalil Travelling ProfessorshipCluj-Napoca, Romania

June 2010

Overview

• Context of 5 Rs of radiobiology and 6 hallmarks of cancer

• Molecular mechanisms of tumour repopulation and targeted therapy approaches

• Reoxygenation as a therapeutic target

• DNA repair and the potential to modulate it for therapeutic gain

• Genetic analysis of the difference between sensitive and resistant tumours

The 5 Rs of Radiobiology

• Repopulation

• Repair

• Reoxygenation

• Redistribution

• Radiosensitivity

The Hallmarks of Cancer

Hanahan and Weinberg 2000

Frameworks of Classical and Molecular Radiobiology

Withers Adv Radiat Biol. 1975; 5: 241-7Steel et al. Int. J. Radiat. Biol. 1989;56: 1045-8

Tumour Repopulation

Time from start of treatment (days)

Tum

our

grow

th r

ate

2010

Dog-leg curve

30

Response to injury

Depletion of tumour cells improves nutrient delivery to survivors

Darwinian selection – surviving cells grow faster

Hyperfractionation

Conventional fractionation

Accelerated hyperfractionation

Concomitant boost

CHART

Split-course accelerated hyperfractionation

Altered Fractionation in Response to Accelerated Repopulation ErbB-receptor family and its ligands

EGFTGF

AmphiregulinHB-EGF

Epiregulin Heregulins

NRG2NRG3

Heregulins-cellulin

Cysteine-richdomains

Tyrosine kinasedomain

ErbBErbB--11Her1

EGFR

ErbBErbB--22Her2neu

ErbBErbB--33Her3

ErbBErbB--44Her4

C-terminus

?



Activation of transmembrane tyrosine kinase receptors

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyrPP

PP

PP

PP

PP

PP

PP

PP

PP

PPTyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

TyrTyr

extracellular ligand extracellular ligand binding domainbinding domain

transmembrane transmembrane domaindomain

intracellular tyrosine intracellular tyrosine kinase domainkinase domain

activation of signaling cascadesactivation of signaling cascades

ligand bindingligand bindingligand bindingligand binding dimerizationdimerization

EGFR as an archetypal growth factor receptor

MAPK

MEK

Gene transcriptionCell cycle progression

PI3-K

RAS RAF

SOS

GRB2

PTEN AKTSTAT

R

KpY

R

pY

pY

K

proliferation/maturation

Survival / anti-apoptosis angiogenesis

metastasis

DNAmyc

Myc

cyclin D1 Cyclin D1

JunFos

P P

PP--EGFREGFR

-IR +2Gy

PP--EGFREGFR

- + EGF

Tumours showing high EGFR expression

EGFR overexpression in human tumors

• NSCLC 40-80%

• Prostate 40-80%

• Gastric 33-74%

• Breast 14-91%

• Colorectal 25-77%

• Pancreatic 30-50%

• Ovarian 35-70%

• Bladder 31-48%

• Renal cell 50-90%

• H&N 80-100%

• Glioma 40-63%

• Oesophageal 43-89%

High expression generallyassociated with

• Invasion

• Metastasis

• Late-stage disease

• Chemo-/Radiotherapy resistance

• Poor outcome

Potential Effects of EGFR Blockade

• Repopulation

• Repair

• Reoxygenation

• Redistribution

• Radiosensitivity

DNA-repair

Effects of blockade of EGFR-signaling

VEGF

angiogenesis MMP9

invasion

PI3K-AKT survival pathway

Pro-proliferative RAS-MAPK pathway

JAK-STAT pathwayregulating gene

transcription

NO DOWNSTREAM SIGNALING

Small molecule inhibitors

Monoclonal antibodies

Akimoto et al. Clin. Cancer Res. 1999; 5: 2884-90

EGFR Status and Local Control in Murine and Human Tumours

Eriksen et al. Int. J. Radiat. Oncol. Biol. Phys. 2004; 58: 561-6



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

euoxiahypoxia

anoxiaTumour blood vessel

Thomlinson and Gray. Br. J. Cancer 1955

02 diffusiongradient

1 2 3 4 5

euoxic

hypoxic

100

10-1

10-2

10-3

OER = 8/3.25 = 2.5

10

RT dose (Gy)

7 8 96



Meta-analysis of hypoxia modification

1.09

(0.93-1.29)

1718391626RT complications

0.93

(0.80-1.07)

2120413821Distant metastasis

1.19

(1.09-1.29)

31351003777Survival

1.29

(1.19-1.41)

4552865265L-R control

ORRT alone (%)RT+sensitiser(%)

PatientsTrialsEndpoint

Overgaard and Horsman. Semin. Radiat. Oncol. 1996; 6: 10-21

Loco-regional Control According to Type of Modifier

2.27

(1.00-5.20)

69841351Transfusion

1.24

(1.12-1.38)

4248597441HCS

1.47

(1.26-1.71)

4959266724HBO/oxygen

ORRT alone (%)RT+sensitiser(%)

PatientsTrialsModifier

L-R Control According to Tumour Site

1.19

(0.85-1.65)

33376248Lung

1.24

(0.93-1.67)

455070712Bladder

1.31

(1.13-1.52)

5865287716Cervix

1.35

(1.20-1.53)

3946425027Head and neck

ORRT alone (%)

RT+sensitiser(%)

PatientsTrialsEndpoint



Hardee et al. PLoS One 2007; 6: e549 Int. J. Radiat. Oncol. Biol. Phys. 2009;73:391-8.

1. No transfusion2. Transfusion

1. No transfusion2. Transfusion

L-RC DSS

VEGF-gene family: VEGF-A,B,C,D,F

VEGF-A: blood vesselVEGF-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)

VEGFs and VEGF-Rs Normalisation of Tumour Vasculature as an Adjunct to RT

DNA Repair – Classical Descriptors

• 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

Targeting DNA Repair

Khanna and Jackson 2001



Homologous recombination - HR Non-Homologous End Joining - NHEJ

Carried out primarily by 7 proteins

HR versus NHEJ

• NHEJ– Repairs most DSB - 80%

– Important for radiosensitivity

– Error prone

– All parts of the cell cycle

– ½ time ~2-4 hours

– Defects rare in cancer

– Proliferating and non-proliferating tissues

• HR– Repairs fewer DSB – 20%

– Important for radiosensitivity

– Error free

– S and G2 phase

– responsible for change in sensitivity in the cell cycle

– ½ time long – 24hours?

– Varies more between cell lines (high in stem cells)

– Defects common in cancer

– Proliferating tissues

ATM Inhibition as a Radiosensitiser

Vehicle, KU58050

KU55933

Hickson et al 2004

PARPi as a Potential Radiosensitiser Strategy (1) PARPi as a Potential Radiosensitiser Strategy (2)



PARPi as a Potential Radiosensitiser Strategy (3)

70 Gy

40%

5%

Radiation doseP

rob

ability o

f tum

ou

r con

trol (%

)

Pro

bab

ility of n

orm

al tissue d

amag

e (%)

Complication-free cure = 35%

Harrington and Nutting, Curr Opin Investig Drugs 2002

Tumour dose-response curve

Normal tissue dose-response curve

Favourable Tumour for RT Cure

Unfavourable Tumour for RT Cure

Radiation dose (Gy)

Prob

ability of tu

mou

r control

Prob

ability of n

ormal tissu

e dam

age

Complication-free cure

70 Gy

20%

5%

30%

• New techniques permit analysis of tumour– DNA profile (genome)

– RNA profile (transcriptome)

– Protein profile (proteome)

– Kinase profile (kinome)

• Bioinformatics allow simultaneous analysis of the interplay of 100s or 1000s of genes

• New prognostic information– Recurrence

– Dissemination

– Response to therapy

Genetic fingerprinting to predict response?

Expression and Tissue Microarray



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 moleculartherapies

• 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


Thursday 17th June 2010 1

Target volume definition in

head and neck cancerDr Christopher Nutting

Royal Marsden Hospital and Institute of Cancer Research

Introduction IHead 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:– OAR with in parallel FSU - 3DCRT does not work!

– OAR with in-series FSU allows clinical gains from partial tissue sparing

Introduction II

Accurate target volume definition is a potential pitfall of head and neck IMRT and is required for:

• Adequate clinical results

• Education and training – Consistency

• Clinical trials - Comparison of outcomes e.g.PARSPORT Trial

Two components:

1. NODAL OUTLINING


Two components:

1. NODAL OUTLINING


NODAL OUTLINING

Robbins Lymph Node classification :

– Level Ia: submental triangle– 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

Patterns of spread documented in large retrospective surgical series.

Sobotta, 1982



NODAL OUTLINING: Problems

• Surgically defined boundaries sometimes difficult to identify on CT/MR

• Neck position is different in radiotherapy patients / compared to surgical series

• Consensus outlining guidelines endorsed by EORTC and RTOG……

• Contrast Enhanced CT scan essential

Level

Cranial Caudal Anterior Posterior Lateral Medial

Ia Mandible Hyoid bone Symphysismenti

Body hyoid bone

Ant. Belly of digastric m.

n.a.

Ib Cranial edge SCM

Hyoid bone Symphysismenti; platysma

Post. edge SCM

Mandible, platysma, skin

Lat. edge of ant. belly DG

II Caudal edge lat. process C1

Caudal edge hyoid bone

SM,ICA,post belly DG

Post edge SCM

Medial edge SCM

Med. edge ICA,PS

III Caudal edge hyoid bone

Caudal edge cricoid cart.

Ant edge SCM, postlatedge SH

Post edge of SCM

Medial edge SCM

Med edge ICA,PSm

IV Caudal edge cricoid cart

2cm cranial to SCJ

Ant edge SCM

Post edge of SCM

Medial edge of SCM

Med edge ICA, PS

V Cranial edge hyoid bone

Cervical transverse vessels

Post edge SCM

Ant edge trapezius m

Platysma, skin

PSm

VI Caudal edge thyroid cartilage

Sternalmanubrium

Platysma, skin

Between trachea and oesophagus

Thyroid gl., skin, SCM

n. a.

Gregoire et al 2002

CONSENSUS OUTLINING GUIDELINES

RETROPHARYNGEAL NODES

Base of skull

to

C3

Midline structure

Sobotta, 1982

medial edge IC

A

RP nodes: Base of skull to cranial edge body hyoid bone

Prevertebral fascia

med

ial e

dge

ICA

Fascia under pharyngeal mucosa

Anterior belly of both digastricmuscles and hyoid bone

Midline structure

Level Ia-SUBMENTAL TRIANGLE

Sobotta, 1982

Body of the hyoid

Level Ia: Mandible to hyoid bone

Symphysis menti/ platysma

Anterior belly of digastric

muscle

Ant

erio

r be

lly

of d

igas

tric

mus

cle



Level Ib-SUBMMANDIBULAR

TRIANGLEAnterior and posterior belly of the

digastric muscle and body of the mandible

Sobotta, 1982

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

Symphysis menti/ platysma

Mandible/platysm

a

Man

dibl

e/pl

atys

ma

Posterior edge SM gland

Lat

eral

edg

e an

teri

or b

elly

of

diga

stri

cm

uscl

eLateral edge anterior belly of digastric

muscle

Level II – UPPER DEEP CERVICAL

NODES

Anatomy: • From carotid bifurcation

(hyoid) to skull base.• Posterior border of the SCM to

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

Level II: Caudal edge lateral process C1 to caudal edge hyoid bone

Level IIa: post border- ant edge SCM

medial edge IC

A, P

Smmed

ial e

dge

SCM

med

ial e

dge

ICA

, PSm

medial edge SC

M

post edge SCM

SM gland, ICA, post belly Digastric

Level III – MIDDLE JUGULAR NODES

Anatomy:

• 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

Level III: Caudal edge hyoid bone -- caudal edge cricoid cartilage

med

ial e

dge

ICA

, PSm

Ant edge SCM , posterolateral edge Sternohyoid

medial edge SC

M

med

ial e

dge

SCM

post edge SCM

medial edge IC

A, P

Sm



Level IV– LOWER JUGULAR NODES

Anatomy:

• From the junction of the omohyoid muscle with the IJV(cricoid level) to the clavicle.

• Posterior border of the SCM to the lateral border of the sternohyoid muscle

Sobotta, 1982

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

Ant edge SCM m

med

ial e

dge

SCM

post edge SCM

medial edge IC

A, P

Sm

medial edge SC

M

med

ial e

dge

ICA

, PSm

Level V– POSTERIOR TRIANGLE NODES

Boundaries: • Anterior border of the

trapezius muscle to Posterior border of SCM

• Skull base to Clavicle

It includes the supraclavicular nodes

Sobotta, 1982


Post edge SCM

Platysm

a

Anterior edge trapezius m.

PSm

PSm

Pla

tysm

a


Post edge SCM

Platysm

a

anterior edge trapezius m.

PSm

PSm

Pla

tysm

a


Post edge SCM

anterior edge trapezius muscle

PSm

Pla

tysm

a



Level V: Supraclavicular nodes Lymph node levels I-V and RPN’s bilaterally

Lymph node levels Ib-V bilaterally

IbII

III

IVV

IbII

III

IVV

Nutting et al 2003

Problems with guidelines

• Post operative neck – where anatomy is rearranged compared to un-operated neck

• Node positive neck – again anatomy is distorted, and spread outside nodes (ECS) commonly occurs

• Controversy over which nodal groups are to be included in target volume for each tumour site

Two components:

1. NODAL OUTLINING



• NO ACCEPTED GUIDELINES

• Sources of information:– Tumour site/ stage

– Tumour natural history

– Anatomical descriptions

– Surgical experience

– Lessons from conventional radiotherapy




• 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

Clinical example:T4N2bM0Hypopharynx

Tumour GTV I

T4N2bM0Hypopharynx

Tumour and node GTV I and II

T4N2bM0Hypopharynx

Tumour and node GTV I and II and CTV I and II (whole organ, and node with margin)

T4N2bM0Hypopharynx

High dose CTV (composite of CTV I and II)

T4N2bM0 Hypopharynx

Add elective CTVs



T4N2bM0 Hypopharynx

3D reconstruction High dose and elective CTVs

OUTLINING OF OARs

• SPINAL CORD

• BRAIN STEM

• OPTIC NERVE

• LENS

• RETINA

• OESOPHAGUS

• ORAL CAVITY, LARYNX, TRACHEA

CTV + 3mm= PTV

EDITING:– PTV edited out of SKIN to avoid necrosis

– Lower dose volumes out of high dose volumes

Preliminary Clinical Results

Patterns of recurrence SCC H&N• Dawson et al, 2000.

PS- IMRT Median FU 27 months (6-60) 58 patients

In high dose volume 10Marginal 2 (ipsilateral electively treated neck)

No recurrences in region of parotid gland

• Chao et al, 2003PS- IMRT Median FU 26 months (12-55) 165 patients

In field/marginal 12Outside 6 (5 lower,1 post neck)

No recurrences in contra-lateral high level 2 nodes (partially spared)

Conclusions I

• Target volume definition is critical component of conformal radiotherapy

• It represents the largest uncertainty in head and neck treatment planning

• International guidelines should be used to define elective lymph node targets



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



Sheila RankinGuy’s & St.ThomasLondon

FDG-PET in head and neck cancer

Romania 2010

Head and Neck cancer

555,000 new cases world wide300,000 deaths per yearLow and medium income countries90% SCCTobacco, Alcohol in 75%Genetic factorsHuman papilloma virus (HPV)

FDG-PET in Head & neck cancer

Indications• Primary extent of tumour• Nodal staging. • Metastases• Treatment planning• Response to treatment – post CRT• Recurrence• Unknown primary

FDG-PET in Oncology

Advantages of functional imaging• Identifies metabolically active tissue• Depend on activity not size• Assess response prior to size change• Quantitative measurements - SUV• Whole body imaging technique• Post treatment anatomic distortion less

significant

Combined PET-CT systemsCT PET

Advantages

•Accurate co-registration

•Decrease overall acquisition time

Disadvantages

• radiation – dose by 1/3 (8mSv)

• contrast/breathing artefacts

Physiologic uptake

MusclesMucosaLymphoid tissuesTonsilsSalivary tissueBenign uptake in thyroid adenomas/

thyroiditis



590 patients. No history head & neck cancerElevated 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

Waldemyers ring, oral floor, larynx, thyroid assessed

Huesner TA. E J Nuc Med Mol 2009 Huesner TA. E J Nuc Med Mol 2009



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%• 11% equivocal

Schoder. Radiology 2004

CTCT from PET/CT

CE CT or non CE CT in FDG/PET

40 patients head & neck cancer

Yoshida K, E J Nuc Med Mol 2009

83%/ 79%53%87%Diagnostic CT

88%/ 90%58%95%Diagnostic MRI

92%/ 90%73%95%Non CE PET/CT

92% /90%75%98%CE PET/CT

N detection/ accuracy

T accuracyT detection

Yoshida K, E J Nuc Med Mol 2009

CE CT or non CE CT in PET/CT

CE HN PET/CT

WB PET/CT

CE CT

91%70%57%Nodal sensitivity

76%79%81%Nodal accuracy

CE HN PET/CT better for small <15mm nodes

Rodrigues, J Nuc Med Mol 2009

CE CT or non CE CT in PET/CTFDG-PET in Head & neck cancer




Pre-operative FDG-PETNo information on

Patterns of local spread

Deep infiltrationBone and cartilage

destructionPerineural spread

Keyes. AJR.1997.169:1663

Extent of tumour

Better information with PET/CT

FDG –PET for synchronous tumoursPan-endoscopy routinely performedSecond primary in 4.5%

• Sensitivity 74%• Specificity 99.7%

FDG PET-CT in 6.1%• Sensitivity 100%• Specificity 95.7%

Because of cost only use PET-CT in advanced disease for distant disease

Hearle Head Neck 2010


Indications• Primary extent of tumour• Nodal staging.• Metastases• Treatment planning• Response to treatment – post CRT• Recurrence• Unknown primary

MRI Versus CT for NodesCT

Sensitivity 88-90%, specificity 39%

PPV 50%, NPV 84%

MRISensitivity 81-82%,

specificity 48%PPV 52%, NPV 79%

Curtin. Radiology.1998



FDG-PET in head & neck cancer

54 patients.SCC oral cavity/oro-pharynx.Assessed for nodal disease

PET CT US/FNASensitivity 96% 85% 64%Specificity 90% 86% 100%In 9 (17%), second primary identified on PET

Stokkel. Annals of Surg.2000;231:229

FDG-PET in Staging22 patientsNodes Sens Spec AccCT 73% 57% 68%PET 93% 100% 95%TumourCT 71%PET 81% and occult tumour

Bruschini Acta Oto Ital 2003

Added value of PET/CT in retro-pharyngeal nodal detection

13False - ve

310False + ve

94.7%83.3%NPV

72.7%33.3%PPV

86.7%60.6%Accuracy

85.7%60.0%Specificity

88.9%62.5%Sensitivity

+ PET/CTCT/MRI

Chu Head & Neck Surg 2009 TP FP

PET/CT

Improves detection

Limitations

Small numbers

Chu Head & Neck Surg2009



Screening for metastases

2-18% at presentationNot screen all patient Risk high if N2 or N3PET- CT more sensitive than PET or CT(63% vs 53% vs 37%)PET-CT cost effective

Uyl de Groot J Nuc Med 2010



SCC in neck nodes

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

Screening for distant tumours

Pyriform fossa cancerFDG-PET in staging

56 patients head and neck cancerPrimary- 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 planningAdvantages• Reduce intra-observer variability of GTV• Reduce size of GTV• Identify tumour missed by CT/MR• Identify areas requiring boostDisadvantages• Poor spatial resolution• False positives due inflammation• Lack of standard segmentation method• 5% change in threshold contour may

increase volume by 200%



Red = GTV on CT

Green = PET visual

Orange = SUV 2.5

Yellow = 40% max intensity

Dk blue = 50% max intensity

Lt blue = adaptive threshold base on signal:background ratio

T4N2

T4N2Troost J Nuc Med 2010

18F FLT (fluorothymidine)Head & Neck cancers show avid uptake

False positives in nodes

Accurately images tumour during RT

FDG influenced by inflammatory response

Troost J Nuc Med 2010

FLT pre RT

Red=GTVct

FLT post RT 8x2Gy

Tumour delineation in HNSCCCT and MRI T2W and T1W + gd - similar volumes GTV FDG < GTVCT

All local recurrences in GTV FDG

Boost dose to GTV FDG within GTVCT

FMISO - amount and level of hypoxia negative correlation with DFS. Recurrence outside baseline hypoxic area

? boost dose to permanent areas of hypoxia

Dirix J Nuc Med 2009

FDGFMISO post RT

PET- CT in treatment planningMetabolic treatment volume of 40ml

predict response> 40ml - lower rate complete response> 40 ml – worse disease free survivalSUV no correlation with outcome

Chung Clin Cancer Research 2009

Definition of metabolic volume difficult especially nodes

Schinagl Radiother Oncol 2009



Management following CRT

Adjuvant ND after CRT is standard of care

Decrease risk of nodal recurrencePrognostic informationIncreased painFunctional disabilityCost



Cost effectiveness of PET/CT in deciding need for ND

Compared 3 strategies using Markov model

• Dissect all patients

• Dissect patients with residual disease on CT

• Dissect patients with RD on PET-CT

Probabilistic sensitivity analysis performed

ND based on RD on PET-CT dominant strategy

PET-CT cost effective $500,000/QALY

Sher Annals Oncol 2009

Monitoring response following chemoradiotherapy

FDG PET at least 8/52 after treatmentNPV = 95%PPV = 71%

NPV 100%PPV 40%Planned neck dissection can be deferredIf CR of primary and negative but palpable

nodes close follow up with PET-CT can be used

Porceddu Head & Neck 2005

Rabalais. Laryngoscope 2009

FDG-PET after DXT

12 patients. 1 month after DXT

Sens Spec PPV NPV

CT/MR 90% 100% 100% 50%

PET 45% 100% 100% 14%

Rogers. Int J Rad oncol 2004

3-6 months after DXT

PET 100% 81% 46% 100%

Conessa Ann Otol Rhin 2004

Role of PET-CT in neck dissection

Clinically No after CRTFor planned ND following CRTScan between 8-11 weeksSensitivity 60%, specificity 36%

• FP – inflammation FN – necrosisNPV 67% PPV 30%Regional recurrence post ND 6% - similar rate

to observationCannot use early PET/CT to predict need for

NDGourin Laryngoscope 2009

Monitoring response following CRTLow tumour SUV post chemoRT

or complete response on CT

correlates with improved survival (tumour NOT nodes)

CT and PET stratify patients into risk groups

Moeller Int J Rad Onc Biol 2010

Prognostic information and PET

Retrospective study of PET performed after RTNodes - NPV 99%, PPV 71%Tumour – NPV 98.7%, PPV 32.4% - especially

larynx. High uptake poor quality of lifePET 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





Recurrent cancer of tongue

2009

2010

2009

Previous Ca Tongue. New palpable nodes ? recurrence





Unknown primary2.3 - 4.2% of all cancersSite identified in only 20% ante mortemCommonest site – lung, pancreas, oropharynxMeta analysis PET/CT tumour detection in

37%False positives

• Lung• Oropharynx

False negatives• breast

Kwee TC Eur Radiol 2009

Blind biopsy 10%

CT/MR guided biopsy 20%

PET guided 40% in one series

10% of +ve PET was –ve on biopsyKeyes.AJR.1997.

Sens 62%, spec 66%, PPV 62%, NPV 62%

Management altered in 50%

Wong Clin Onc 2003

FDG-PET in unknown primary

Blind biopsy 10%CT/MR guided biopsy 20%PET guided 40% in one series10% of +ve PET was –ve on biopsy

Keyes.AJR.1997.

16 patients CT/MR negativePET TP in 8, FN in 2, 6 no tumour on F/USens 62%, spec 66%, PPV 62%, NPV 62%Management altered in 50%

Wong Clin Onc 2003

PET/CT in Head and Neck Cancer

ConclusionsFDG- PET used for:• Nodes• Metastases• Recurrence/Response• Unknown primaryNew PET tracers



Inverse planning for intensity modulated radiation therapy

Romania June 2010 Romania June 2010

Steve WebbHead

Joint Department of PhysicsInstitute of Cancer Research (University of London)

andRoyal Marsden NHS Trust

Inverse planning for IMRT

Summary of key points on Summary of key points on inverse planninginverse planning

The The key historical stageskey historical stages leading to inverse leading to inverse planning were: planning were: (i) (i) <1920s<1920s: no planning, : no planning, (ii) (ii) 1920s1920s--1960s1960s ““hand planninghand planning”” (overlay of (overlay of isodoseisodose curves on transparencies), curves on transparencies), (iii)(iii) 1960s1960s computer planning (firstly in 2D, computer planning (firstly in 2D, then in 3D). This was then in 3D). This was ““forward planningforward planning””, , (iv) (iv) 19821982 first analytic inversefirst analytic inverse--planned planned problem, problem, (v) (v) 19881988 Censor and Censor and BrahmeBrahme’’ss analytic analytic inversion techniques, inversion techniques, (vii) (vii) 19881988--20102010 explosion of techniques for explosion of techniques for inverse planning, inverse planning, (viii) (viii) 19921992 first commercial inversefirst commercial inverse--planning planning system, (ix) system, (ix) 20102010 most companies offer (in one most companies offer (in one form or another) form or another) ““inverse planninginverse planning”” ..

The Royal The Royal MarsdenMarsden Hospital developed Hospital developed one of the firstone of the first--ever computer treatment ever computer treatment planning systems planning systems –– the the RAD8RAD8 in 1972. in 1972. Thousands of machines were sold. This Thousands of machines were sold. This enabled physicists to do (2D) enabled physicists to do (2D) ““forward forward planningplanning”” in realistic time.in realistic time.

““Forward planningForward planning”” means means ““informed trial, informed trial, error and reerror and re--trialtrial””. Beam type, energy, number . Beam type, energy, number are chosen and the planner adjusts are chosen and the planner adjusts orientations and orientations and beamweightsbeamweights until an until an acceptable plan is found. acceptable plan is found.

Combined with fieldCombined with field--shaping (via MLC or shaping (via MLC or blocks) this is still the workhorse technique blocks) this is still the workhorse technique today for many clinical situations. It works at today for many clinical situations. It works at the level of assuming patient geometries are the level of assuming patient geometries are generically similar.generically similar.



““Inverse planningInverse planning”” (as its name (as its name suggests) is the reverse process. The suggests) is the reverse process. The planner specifies the required 3D dose planner specifies the required 3D dose distribution including PTV and OAR distribution including PTV and OAR requirements and constraints. requirements and constraints.

A computer algorithm then finds a A computer algorithm then finds a beambeam--configuration solution best configuration solution best matched to the prescription. matched to the prescription.

Note:Note:

1.1. Inverse planning can be applied to (non IMRT) Inverse planning can be applied to (non IMRT) geometrically conformal CFRT. geometrically conformal CFRT. ““Inverse planningInverse planning””does not mean does not mean ““planning IMRTplanning IMRT””..

2.2. ““Inverse planningInverse planning”” is largely synonymous with is largely synonymous with ““plan constrained optimisationplan constrained optimisation””. .

3.3. Most physicists believe inverse planning is Most physicists believe inverse planning is absolutely necessary for IMRT. Some disagree and absolutely necessary for IMRT. Some disagree and direct forward techniques are published.direct forward techniques are published.

4.4. Inverse planning is characterised by some wellInverse planning is characterised by some well--defined cost function. Physicists may argue over the defined cost function. Physicists may argue over the choice but once specified it is this which drives the choice but once specified it is this which drives the optimisation and the photonoptimisation and the photon--tissue interactions which tissue interactions which

determine the outcome.determine the outcome.

5.5. The principles of all inverse planning are The principles of all inverse planning are the same; the differences lie in the detail.the same; the differences lie in the detail.

6.6. Inverse planning does not deliver Inverse planning does not deliver ““the the optimum planoptimum plan”” because some parameters (e.g. because some parameters (e.g. numbers of beams, beam energy) are fixed numbers of beams, beam energy) are fixed ahead of the optimisation. It delivers the ahead of the optimisation. It delivers the ““constrained optimum planconstrained optimum plan””..

7.7. From about 1988 to 1998 most inverse plan From about 1988 to 1998 most inverse plan algorithms (PEACOCKPLAN/CORVUS algorithms (PEACOCKPLAN/CORVUS excepted) were oneexcepted) were one--off local developments in off local developments in a research setting. From 1998 this dramatically a research setting. From 1998 this dramatically changed and most planning system companies changed and most planning system companies offer inverse planning.offer inverse planning.

8.8. If the goal of optimised inverse planning If the goal of optimised inverse planning was ever to was ever to ““replace the human plannerreplace the human planner””nothing could now be further from the truth. nothing could now be further from the truth. Inverse planning has opened up more choices Inverse planning has opened up more choices but provided sophisticated tools to navigate but provided sophisticated tools to navigate the choices. the choices.

9.9. Inverse planning is only part of the Inverse planning is only part of the ““radiotherapy physics chainradiotherapy physics chain””. Given . Given ““garbagegarbage--in garbagein garbage--outout”” concept, the clinical concept, the clinical outcome depends, not only on the planning, outcome depends, not only on the planning, but on the determination and specification of but on the determination and specification of PTV, PTV, OARsOARs, dose calculation algorithm, dose , dose calculation algorithm, dose delivery technique, verification of accuracy, delivery technique, verification of accuracy, biological estimation of outcome etc.biological estimation of outcome etc.

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 withautomation:

(1) use of larger number of fields

(2) use of non-coplanar fields

(3) use of B.E V-shaped M.L.C. fields

(4) I.M.B.s.

Symbolising the Symbolising the essence of IMRTessence of IMRT



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

2 broad classes:

(1) Analytic techniques – inverse computed tomography

(2) Iterative techniques – including simulated annealing

Some optimisation tools combine both

Simulated annealing: general concepts

Iterative optimisation technique to find global minimum of a cost function in the presence of potential multiple local minima.

Used in a variety of fields

First used in medical imaging by Barrett (~1983) to minimise a quadratic cost function

First used for SPECT by Webb (~1987)

Introduced to radiotherapy treatment planning by Webb (~1988)

Further developed by Mohan (New York).

Beam sinogramBeam sinogram All 2D imagesAll 2D images

AnalogyAnalogy

dosedose beamsbeams

S.P.E.C.T.S.P.E.C.T.γγ cameracamera



Application to radiotherapy treatment planning

Computation of I.M.B. profiles

Medical imaging analogy

Consider (for convenience) a quadratic cost function

212(

rr DDV n

rpn

Cost = (rImportance (r) [Dp(r) – Dn (r)]2)½

where Dp (r) is dose prescription

and Dn (r) is dose at nth iteration

Digital dose prescriptionDigital dose prescription Dose with optimised beamsDose with optimised beams

Aim : minimum VAim : minimum V

Simulated annealingSimulated annealingGrain of beam Grain of beam element weightelement weight

Acceptability of positiveAcceptability of positive--potential changespotential changes

Probability of acceptance = exp(Probability of acceptance = exp(--ΔΔV/kT)V/kT)

ΔΔV = potential change due to grain placementV = potential change due to grain placement

K = BoltzmannK = Boltzmann’’s constants constant

T = temperatureT = temperature

Strategy: start at high temperature and then cool such that T isStrategy: start at high temperature and then cool such that T is reduced reduced slower than 1/ slower than 1/ lnln (n)(n)

This guarantees convergence to a global minimumThis guarantees convergence to a global minimum

Temperature T high TTemperature T high T

exp(exp(--ΔΔV/V/kTkT))

If If ΔΔV < 0 accept grainV < 0 accept grain

If If ΔΔV > 0 accept grain with probability exp (V > 0 accept grain with probability exp (-- ΔΔV/V/kTkT))

(T is temperature and k is Boltzmann(T is temperature and k is Boltzmann’’s constants constant

Global minimum Global minimum (crystalline state)(crystalline state)Crystal analogyCrystal analogy

Decreasing potential energyDecreasing potential energy

TrapTrap

Amorphous Amorphous statestate

(local (local minimum)minimum)

skierskier

++veve ΔΔVV

--veve ΔΔVV

--veve ΔΔVV

traptrap



Dose is surrogate for biological outcome

TCPn = f1 Dn (r) r part of P.T.V.

NTCPn = f2 Dn (r) r part of O.A.R.

So:1. Maximise TCP subject to maximum NTCP.2. Minimise NTCP subject to minimum TCP.3. Maximise TCP x (1-NTCP).4. Combine dose and biological cost in some way?

Note a physical parameter cannot be a goal for optimisationand a constraint at the same time.

Arguments for biological cost functions

The aim of radiotherapy!

Argument against

Models relatively new (and only models, not “real”physical quantity)

Data are based on limited observations

An “across the pond” diversity U.K. vs U.S. approach

Practicalities

S.A. substitutes only for one part of the planning process.

Still needs to be fed:

1. P.T.V., O.A.R. from 3D C.T., M.R, P.E.T., S.P.E.C.T.

2. Dose to each dose-space voxel per unit beamweight

3. Biological model and data4. Prescription and constraints on plan and

beamweights

Results (3D dose distributions) evaluated by same tools as results from forward planning:

i.e. D.V.H.isodoses3D shaded surface dose distributionsdose ribbonsa posteriori T.C.P., N.T.C.P. etc.

S.A. should be part of an integrated 3D T.P. system

Required features of S.A.

1. + and – grains : mechanism to “undo” structure

2. grain size reduction

3. beamweights constrained positive (c.f. analytic inversion!)

4. care to computer aspects of C.F. calculation – at heart of optimisation

5. other beamweight constraints

Downsides

Simulated annealing’s flexibility is also its weakness

It needs tuning

Careful choice of grain sizes, number of iterations,Type of C.F.

Cooling schemes

III conditioned problems have C.F.s with a broad region of shallow curvature in vicinity of minimum = many different solutions (beamweight configurations) for same cost.



The ideal scenario which no planning system currently offers

Most treatment planning algorithms were developed as standalone facilities to do specific tasks. Commercial systems generally implement the subset of planning codes for situations that interest them. No system has everything so comparisons are difficult on the same patient cases with the same tools.

The ideal system would provide:

…………

The ideal system would provide:

Forward and inverse planning together. Planning for MLC-shaped fields and for 2D IMBs. Planning for protons and heavy particles. Ability to switch in different cost functions and indeed

different algorithms for inverse planning. Compatability with all manufacturers’ 3D imaging formats. Variety of exploration tools for 3D dose distributions. Computation of biological cost.

There is no such thing as an optimum plan!

An algorithm will only generate a plan which is “best”according to the constraints provided.

It is well known that the inverse treatment planning problem is ill-conditioned. This means many different IMB sets can give much the same 3D dose distribution. (The “Sticky marble in a flat-bottomed bowl” story).

There is actually no need for the optimum plan (if it existed). What is needed is an acceptable plan = a much better plan that could be had without IMBs.

Conclusion

S.A. works

Very flexible tool

Not as slow as it once was

“A hard car to drive” – tuning all important

Detailed descriptions of Detailed descriptions of both theoretical and both theoretical and

practical IMRT + huge practical IMRT + huge lists of primary lists of primary

references can be found references can be found in these 4 sequential in these 4 sequential

booksbooks

19931993 19971997

20002000

20042004

Day 2 Session 2 Lecture 1012:00 noon


IMRT planning: IMRT planning: strategies for improving poor strategies for improving poor

plans, common errorsplans, common errors and and plan assessmentplan assessment

Dr Catharine Clark

Improving the planImproving the plan–– Before, during and after optimisationBefore, during and after optimisation

Plan assessmentPlan assessment–– Volumes, beams and dose distributionsVolumes, beams and dose distributions–– FluencesFluences and leaf motionsand leaf motions

IntroductionIntroduction

Adapting volumesAdapting volumes

Addition of margins to volumesAddition of margins to volumes Editing of volumesEditing of volumes

–– can define constraints separately for can define constraints separately for overlap regionoverlap region

Creation of Creation of ‘‘dummy volumesdummy volumes’’


Exclusion of build-up area to ensure skin sparing

Edit overlapping volumes

Dummy volumes to avoid unwanted hotspots

Expansion of OAR to maximise sparing

Adapting volumesAdapting volumesExpansion of PTV to improve coverage

Adapting volumesAdapting volumesAdditional non critical ‘dummy’volume




Difference in rectal sparing with addition of Rectum-PTV

Symmetric in sup / Symmetric in sup / infinf–– maximise use of 5mm leavesmaximise use of 5mm leaves

Avoid too much Avoid too much asymetryasymetry in X jawsin X jaws–– Can cause problems for split beamsCan cause problems for split beams

IsocentreIsocentre positionposition

IsocentreIsocentre positionposition

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 fieldsPartial blocking of fields

Careful beam angle choice avoids treating through couch bars


Jaws positioned off cord to improve cord sparing




Acceptable Dose Distribution?Acceptable Dose Distribution?

E.g in overlap region or close E.g in overlap region or close proximity of target to OARproximity of target to OAR

Dose

TargetOARs

Unhappy with dose to OAR?Unhappy with dose to OAR?

Dose

TargetOARs

Acceptable Dose Distribution?Acceptable Dose Distribution?

Increase weight / stricter objective

Decrease weight / relax objective

Unhappy with target coverage?Unhappy with target coverage?

Dose

TargetOARs

Increase weight / stricter objective

Decrease weight / relax objective

Acceptable Dose Distribution?Acceptable Dose Distribution? Working with constraintsWorking with constraints

Plan AnalysisPlan Analysis

Following a Following a full 3D full 3D calculation for calculation for Dose volume Dose volume histogramshistograms–– compare to compare to

plan plan acceptance acceptance criteriacriteria

Plan AnalysisPlan Analysis

Still important to review the dose distribution

check for hotspots in uncontoured tissue

check that reduced PTV doses occur in appropriate place, i.e. in regions of overlap with OARs



Hotspot locationHotspot location

Be realistic Be realistic –– hotspots happenhotspots happen–– small reduction may small reduction may

helphelp Check locationCheck location

–– Inside target volumeInside target volume–– In In uncontoureduncontoured tissuetissue–– In a sensitive regionIn a sensitive region

Hotspot location and reductionHotspot location and reduction

108.7% 107.1% away from mucosa

Improving the PlanImproving the Plan

Delineating hotspotsDelineating hotspots

Improving the PlanImproving the Plan

Dose paintingDose painting

IMRT plan assessmentIMRT plan assessment

VolumesVolumes PrescriptionPrescription BeamsBeams IsocentreIsocentre Dose distribution and coverageDose distribution and coverage FluencesFluences Leaf motions and split fieldsLeaf motions and split fields MU and average leaf gapMU and average leaf gap

Volumes and dose distributionVolumes and dose distribution



Beam orientationBeam orientation

Anterior (0°)

RPO (240°)

RAO (300°)

LAO (60°)

LPO (120°)

Dose distributionsDose distributions

Check dose Check dose coverage against coverage against primary and primary and elective elective prescriptionsprescriptions

Check in all planesCheck in all planes

Matches treated volumesMatches treated volumes Minimal hotspotsMinimal hotspots Check sufficient overlap of split Check sufficient overlap of split

sectionssections Check sections 0 and 1 create totalCheck sections 0 and 1 create total

FluenceFluence AssessmentAssessment

Leaf motionsLeaf motions

Run leaf motionsRun leaf motions Check average leaf gapCheck average leaf gap

–– Ideally < 2cmIdeally < 2cm

Check MUCheck MU–– High MU can indicate delivery problems High MU can indicate delivery problems

and small leaf gapsand small leaf gaps

Look for tongue and grooveLook for tongue and groove



Tongue and grooveTongue and groove

?

Improving the plan summaryImproving the plan summary

Adaptation of volumes including Adaptation of volumes including dummy volumesdummy volumes

Balancing constraints and prioritiesBalancing constraints and priorities Delineating and painting hotspotsDelineating and painting hotspots

Plan assessment summaryPlan assessment summary

DVH and dose distribution togetherDVH and dose distribution together On screenOn screen Check against planned constraintsCheck against planned constraints Verification via calculation or Verification via calculation or

measurementmeasurement



Verification of Treatment DeliveryRole of imaging

Helen McNair

Research Radiographer

Royal Marsden Foundation Trust and Institute of Cancer Research

Why verify?

Detect gross errors

Eliminate systematic errors

Reduce random errors

Why verify?

Detect gross errors

Incorrect patient, anatomical site or patient orientationIncorrect field size, shape or orientation

Incorrect isocentre position of unacceptable magnitude

Eliminate systematic errors

Arise from equipment – affect all patients

Arise from set up – affects one patient

Why verify?

Reduce random errors

Organ motion

Daily set up variation

Why verify? Process

Reference image

Image acquisition

Image registration

Decision



Process

Reference image

Image acquisition

Image registration

Decision

Quality of Reference Image

2.5mm slice thickness

2.5mm DRR 1.25mm DRR


Small slice thickness for good resolution

Increased time on treatment unit on day 1

Mark reference at CT and isocentre on set


Process

Reference image

Image acquisition

Image registration

Decision

Before image acquisition



Check filmsSnap shot

Image acquisition

Manual registrationElectronic Portal Imaging

Image acquisition

Single exposure

Image acquisition

enhanced

Image acquisition

Open fieldDouble exposure or

Image acquisition

Length of scan; Field of View

Interruptions

Off set isocentres

Image acquisition



Image Quality

Low dose scan – 2mGy

High dose scan – 3.9mGy

Process

Reference image

Image acquisition

Image registration

Decision

Anatomy for template

Base of skull

Vertebral bodies (anterior borders)

Pituitary fossa

Clavicles

Nasal septum

Sinuses

Vertebral bodies

Stable radiopaquestructures

Anatomy for template

Manual

Image registration

Region of interest

Image registration



Automatic -incorrect

Image registration

Automatic - Correct

Image registration

Image registration

Check match- Colour wash

Image registration

Check match - Cut view

Image registration

Check match –Soft tissue changes

Image registration

Check match –Soft tissue changes



Image registration

Check match –Tumour changes

Image registration

Check match –Tumour changes

Process

Reference image

Image acquisition

Image registration

Decision - protocols

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Correct for error

SAL- Shrinking Action Level

Check within tolerance




Off line protocols


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Correct for systematic error

NAL- No Action LevelOff line protocols






Less time treatment time involved

More time for image registration

Reduces systematic error which have a greater impact on treatment margins than random errors

de Boer H et al . 2001 de Boer JC, Heijmen BJ 2002.

Off line protocols



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On line protocols

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Correct for error Time pressure for image registration

Can reduce random as well as systematic errors

Brock K 2002Van de SJ 1998

On line protocols

Alignpatient

Start treatment

Imagepatient

Finishtreatment

Correction Treatment time

Image time

On line correctionBack up

Difference in CBCT and EPI

< 0.0010.7 (2.4)Superior/Inferior

p valueMean (SD)

Borst IJROBP 2007

Guidelines Accuracy and reproducibility

Determine random and systematic errors

Reference image

Image quality

Image registration

Effective protocols

Training and competency assessment



Imaging the ThyroidImaging the Thyroid

Dr Julie Olliff Dr Julie Olliff University Hospital BirminghamUniversity Hospital Birmingham


Role of ImagingRole of Imaging

Characterisation of a neck massCharacterisation of a neck mass Assessment of the patient with abnormal Assessment of the patient with abnormal

thyroid functionthyroid function Assessment of the multiAssessment of the multi--nodular goitrenodular goitre Assessment of the incidental thyroid Assessment of the incidental thyroid

nodule nodule Staging of proven malignancyStaging of proven malignancy Diagnosis of recurrent cancerDiagnosis of recurrent cancer

Characterisation of neck massCharacterisation of neck mass

Ultrasound Ultrasound Anatomy Anatomy Solid or cysticSolid or cystic Single or multipleSingle or multiple Blood flowBlood flow Assessment of cervical lymph nodesAssessment of cervical lymph nodes FNA/biopsyFNA/biopsy

Neck massNeck mass

CongenitalCongenital Arrest of descentArrest of descent OverdescentOverdescent Agenesis/Agenesis/hemiagenesishemiagenesis Incomplete degeneration of Incomplete degeneration of thyroglossalthyroglossal duct duct

with fistulous tract or with fistulous tract or thyroglossalthyroglossal cystcyst

Neck massNeck mass

Autoimmune disease and Autoimmune disease and thyroiditisthyroiditis Graves Disease Graves Disease –– often non specific. Thyroid often non specific. Thyroid

enlarged, enlarged, hyperechoichyperechoic, without discrete , without discrete nodules, increase in nodules, increase in vascularltyvascularlty..

HashimotoHashimoto’’s s thyroiditisthyroiditis –– size variable. size variable. Diffusely abnormal Diffusely abnormal echotextureechotexture. In end stage . In end stage may be small and may be small and fibroticfibrotic..

NonNon--toxic goitretoxic goitre

? Airways obstruction? Airways obstruction ? Anatomical delineation? Anatomical delineation Assessment of nodulesAssessment of nodules



Prevalence of thyroid nodulesPrevalence of thyroid nodules

Prevalence of thyroid nodules Prevalence of thyroid nodules -- 50% at 50% at postmortempostmortem –– Mortensen 1955Mortensen 1955

Prevalence on US 67% Prevalence on US 67% -- EzzatEzzat 19941994 Prevalence of occult cancer 2% Prevalence of occult cancer 2% -- BisiBisi 19891989

Diagnosis of thyroid nodulesDiagnosis of thyroid nodules

CystsCysts Colloid noduleColloid nodule ThyroiditisThyroiditis Benign follicular neoplasmBenign follicular neoplasm Thyroid carcinomaThyroid carcinoma

Increased risk of malignancyIncreased risk of malignancy

CalcificationCalcification HypoechogenicityHypoechogenicity Irregular marginsIrregular margins Absence of haloAbsence of halo Predominantly solidPredominantly solid Tall shape AP:T > 1Tall shape AP:T > 1 intraintra--nodule nodule vascularityvascularity Size not a good predictorSize not a good predictor

Evaluation of thyroid nodulesEvaluation of thyroid nodules

No blood flow = no malignancyNo blood flow = no malignancy PerinodularPerinodular flow = no malignancy (2 flow = no malignancy (2

suspicious/65)suspicious/65) Risk of malignancy increases as Risk of malignancy increases as

intranodularintranodular flow becomes more dominantflow becomes more dominant

Chammas et al Otolaryngol 2005;132:874

Detection of Detection of incidentalomasincidentalomas (ITN) (ITN) and risk of malignancyand risk of malignancy

44--8% palpation8% palpation 50% autopsy (Mortensen et al 1955)50% autopsy (Mortensen et al 1955) 50% on US in patients >40years (50% on US in patients >40years (MazzaferriMazzaferri etaletal 1993)1993) 67% on US in 97 pts with no known thyroid disease 67% on US in 97 pts with no known thyroid disease

((EzzatEzzat et al 1994)et al 1994) 63/166 ITN in unselected CT our data 63/166 ITN in unselected CT our data >11.3 % prevalence of malignant or potentially >11.3 % prevalence of malignant or potentially

malignant lesions among incidental thyroid abnormalities malignant lesions among incidental thyroid abnormalities detected on CT detected on CT ShettyShetty et al 2006et al 2006

734 patients CT734 patients CT-- 123 pts found to have ITN. 120 had 123 pts found to have ITN. 120 had histology 15 were malignant (12.5%) Yoon et al 2008histology 15 were malignant (12.5%) Yoon et al 2008

Incidental thyroid nodules on FDG Incidental thyroid nodules on FDG PETPET

Systematic review Systematic review –– ShieShie et al 2009et al 2009 18 articles18 articles 55,160 patients55,160 patients 571 (1%) unexpected focal thyroid abnormality571 (1%) unexpected focal thyroid abnormality 322 diagnostic confirmation322 diagnostic confirmation 200 (62.1%) benign200 (62.1%) benign 107 (33.2%) malignant (papillary cancer 82.2%)107 (33.2%) malignant (papillary cancer 82.2%) 15 (4.7%) no clear diagnosis15 (4.7%) no clear diagnosis



Thyroid nodules and USThyroid nodules and US

494 patients with nodules on US494 patients with nodules on US Nodules 8Nodules 8--15mms had FNA 15mms had FNA FNA success rate (81%)FNA success rate (81%) 402 patients had sufficient material402 patients had sufficient material 107/402 (27%) suspicious107/402 (27%) suspicious Histology after surgery 31/107 =malignantHistology after surgery 31/107 =malignant 31/402 (7.7%)31/402 (7.7%)

PapiniPapini et al 2002et al 2002

Malignant features on USMalignant features on US

Solid, Solid, hypoechoichypoechoic 1.Irregular blurred margins1.Irregular blurred margins 2. 2. IntranodularIntranodular vascular patternvascular pattern 3.Microcalcification3.Microcalcification Independent risk factors for malignancyIndependent risk factors for malignancy HypoechoicHypoechoic ++1, 2, or 3 1, 2, or 3 predicted 87% of malignant predicted 87% of malignant

nodulesnodules Using 1cm as cutUsing 1cm as cut--off for FNA 12/31 (39%) cancers off for FNA 12/31 (39%) cancers

would be missedwould be missed Size not accurate in differentiating benign from Size not accurate in differentiating benign from

malignantmalignant

Papini et al 2002

US risk featuresUS risk features

450 consecutive patients undergoing FNA of 450 consecutive patients undergoing FNA of incidentally discovered nodulesincidentally discovered nodules

94/450 underwent surgery94/450 underwent surgery 20/94 = cancer20/94 = cancer Solid Solid hypoechoichypoechoic only predictor of malignancyonly predictor of malignancy FNA success rate >1cm 85%, <1cm 69%FNA success rate >1cm 85%, <1cm 69% FNA should be performed on all solid FNA should be performed on all solid hypoechoichypoechoic

nodules >/= 1cmnodules >/= 1cmLeenhardtLeenhardt 19991999

US FNAUS FNA

Overall incidence of thyroid cancer in nodules Overall incidence of thyroid cancer in nodules selected for FNA 9.2selected for FNA 9.2--13%13%

Number of nodules present does not alter Number of nodules present does not alter overall cancer rate per patient but will decrease overall cancer rate per patient but will decrease likelihood of each nodule as the number of likelihood of each nodule as the number of nodules rise.nodules rise.

Cancer will be in nonCancer will be in non--dominant nodule in dominant nodule in approx. one thirdapprox. one third

Nodule size is not predictive of malignancyNodule size is not predictive of malignancy

US FNA consensus statementUS FNA consensus statement

SolidSolid-- high sensitivity but low PPV 15.6high sensitivity but low PPV 15.6--27%27%

MicrocalcificationMicrocalcification --PPV 41.8PPV 41.8--94% but low 94% but low sensitivity present in 26.1sensitivity present in 26.1--59.1%59.1%

Colour flow may be helpfulColour flow may be helpful 1cm selected to decrease numbers and 1cm selected to decrease numbers and

unsure about effect on life expectancy of unsure about effect on life expectancy of lesions <1cm.lesions <1cm.

Management of thyroid nodules detected at US:Society of Radiologists in US consensus statement Frates et al 2005

Consensus statementConsensus statementSolitary noduleSolitary nodule >1cm if >1cm if microcalcificationmicrocalcification presentpresent >1.5cms solid or coarse calcification>1.5cms solid or coarse calcification

Nodule >2cmNodule >2cm Mixed solid/cysticMixed solid/cystic Cystic but with a solid mural componentCystic but with a solid mural component Substantial growthSubstantial growth



Consensus statementConsensus statementMultiple nodulesMultiple nodules Consider FNA of one or more nodules using Consider FNA of one or more nodules using

above criteriaabove criteria FNA is likely unnecessary in diffusely enlarged FNA is likely unnecessary in diffusely enlarged

glands with multiple nodules of similar US glands with multiple nodules of similar US appearance without intervening normal appearance without intervening normal parenchymaparenchyma

Presence of abnormal lymph nodes overrides US Presence of abnormal lymph nodes overrides US appearance of thyroid noduleappearance of thyroid nodule

Where are we now?Where are we now?

IncidentalomasIncidentalomas on PET with high SUVon PET with high SUV ““clinicians should be cautious about the management of clinicians should be cautious about the management of

small or incidentally diagnosed nodules in primary care. small or incidentally diagnosed nodules in primary care. It may be prudent to refer to secondary care for further It may be prudent to refer to secondary care for further investigation, such as US guided aspirationinvestigation, such as US guided aspiration”” MehannaMehanna et et al 2009 BMJal 2009 BMJ

166 scans covering all/part of thyroid, 63 pts had ITN. 166 scans covering all/part of thyroid, 63 pts had ITN. 3000 over one year from CT. US 3000 over one year from CT. US ££90, FNA 90, FNA ££270 >1 270 >1 million. ITN>1cm =25 patients extra per week for million. ITN>1cm =25 patients extra per week for USFNA from CT alone. This does not include costs for USFNA from CT alone. This does not include costs for surgery.surgery.

IncidentalomaIncidentaloma on CT or US potential for massive spend, on CT or US potential for massive spend, anxiety for low return in terms of anxiety for low return in terms of QUALYQUALY’’ss

HELP!HELP!

Diagnosis of thyroid cancerDiagnosis of thyroid cancer

UltrasoundUltrasound US alone is not reliable in differentiating benign US alone is not reliable in differentiating benign

from malignant nodules from malignant nodules BUT used to guide or in combination with FNAC BUT used to guide or in combination with FNAC

is the best available techniqueis the best available technique Unreliable for follicular and Unreliable for follicular and HurthleHurthle cell nodulescell nodules

Staging thyroid cancerStaging thyroid cancer

US useful for staging small primary US useful for staging small primary tumours and lymph nodestumours and lymph nodes

MRI, CT or either demonstrate extraMRI, CT or either demonstrate extra--thyroidal or extrathyroidal or extra--capsular extensioncapsular extension

MRI and CT (PETCT) used to demonstrate MRI and CT (PETCT) used to demonstrate distant metastasesdistant metastases

ThyroidThyroidCT and MRICT and MRI stage local diseasestage local disease

extra capsular extensionextra capsular extension assessment of superior assessment of superior mediastinummediastinum

retrosternalretrosternal extension and nodes extension and nodes (VII)(VII)

involvement of larynx, trachea, involvement of larynx, trachea, oesophagus, major vessels and skinoesophagus, major vessels and skin

lymph node involvement (levels Ilymph node involvement (levels I--VII)VII) distant metastasesdistant metastases

ThyroidThyroid

papillary carcinomapapillary carcinoma lymph node involvement commonlymph node involvement common

50% at diagnosis50% at diagnosis small, cystic ,haemorrhagic, calcifiedsmall, cystic ,haemorrhagic, calcified

distant metastasesdistant metastases 44--7% at diagnosis7% at diagnosis lungs, bone, CNSlungs, bone, CNS



ThyroidThyroid

follicular carcinomafollicular carcinoma lymph node involvement less lymph node involvement less

commoncommon 22--10%10%

distant metastases commonerdistant metastases commoner USUS-- solid solid isoechoicisoechoic 52%, and 52%, and

hypoechoichypoechoic 42%42% more frequently invades vesselsmore frequently invades vessels

MedullaryMedullary carcinomacarcinoma

Para follicular or C Para follicular or C –– cells (neural crest cells (neural crest origin)origin)

8080--90% express 90% express calcitonincalcitonin (better (better prognosis)prognosis)

Calcification may be seen in primary, Calcification may be seen in primary, nodes and metastasesnodes and metastases

May be thallium or gallium avidMay be thallium or gallium avid MEN ll1 and MEN ll1 and llbllb

Recurrent diseaseRecurrent disease

NM used mainly for demonstration of NM used mainly for demonstration of residual/recurrent differentiated disease residual/recurrent differentiated disease after after thyroidectomythyroidectomy, including , including medullarymedullarythyroid cancerthyroid cancer

FDG PET has 82% sensitivity for FDG PET has 82% sensitivity for demonstrating residual/recurrent disease demonstrating residual/recurrent disease (James 1999)(James 1999)

CT/MR anatomical localisationCT/MR anatomical localisation

PETPET

Tumour dedifferentiation may lead to Tumour dedifferentiation may lead to decreased or lost iodinedecreased or lost iodine--accumulating accumulating abilityability

Negative INegative I--131 scan but elevated human 131 scan but elevated human serum serum thyroglobulinthyroglobulin levellevel Hung et al Hung et al EndocrEndocr Res 2003 29:169Res 2003 29:169

May miss May miss miliarymiliary pulmonary pulmonary metsmets

Frilling et al Ann Frilling et al Ann SurgSurg 2001;234:8042001;234:804

Differentiated thyroid cancerdetection of recurrent disease in patients withelevated thyroglobulin levels and a negative radio-iodine scan

FDG PETsensitivity 82-94% specificity 88-100%

FDG PET-CT indications (non-SCC H&N)

Medullary thyroid cancerdetection of recurrent disease

FDG 85 patientssensitivity 78% specificity 79%superior to other techniquesuseful independent of serum calcitonin

Source: Diehl et al EJNM 2001



ConclusionConclusion There is increasing evidence that US has There is increasing evidence that US has

a role to play in the characterisation of a role to play in the characterisation of thyroid nodulesthyroid nodules

CT and MRI can be used to stage CT and MRI can be used to stage thyroid cancerthyroid cancer

Nuclear medicine and US can be useful Nuclear medicine and US can be useful in the diagnosis of recurrencein the diagnosis of recurrence

CT, PET/CT, PET/CTandCTand MRI used in the MRI used in the anatomical localisation of recurrenceanatomical localisation of recurrence

CT and MRI used prior to surgery for CT and MRI used prior to surgery for large large multinodularmultinodular goitregoitre



PET in Oncology FDG and beyond

Dr S C Rankin

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

Monitoring effects of drug delivery

The perfect tracer

• Easy to make and cheap

• High yield

• High specific activity

• Only binding to the abnormality in question -high specificity to target

• Rapid binding and stable

• Rapid clearance from background

• Early imaging

• No reactions in the patient - no toxicity

• low radiation dose

Positron Emission Tomography

Positron

Positron combines with electron and annihilates

Two anti-parallel511kEV photons produced

Courtesy of

Dr Michael Hofman

Glucose vs. FDG ( 218 Fluoro deoxy glucose)

Glucose

FDGFDG FDG FDG -- 6 6 -- POPO44

Glycogen

G - 1 - PO4

G - 6 - PO4

F - 6 - PO4

CO2 + H2O

Blood

HEXOKINASE

Tissue

HEXOKINASE

G-6-P

FDG-PET in OncologyTechnique• Positron 511 KeV. 2 emitted at 1800

• Transmission scan – attenuation correction. SUV data

• Emission scan• Good contrast resolution• Spatial resolution 5-7 mm



FDG-PET in OncologyTechnique• 370 M Bq injected IV• Limited by dose to bladder wall• Uptake decreased if glucose elevated

– Insulin – FDG to fat and muscle• Fast 4 -18 hours • SUV=FDGregion/FDGdose Body Wt• Tumour SUV 2-20

Cerebral cortex, caudate nucleus

Cardiac. If fasting - 80% no uptake

Renal tract

Thymus in children

Bone marrow

GI tract

Breast – lactating

Thyroid

Normal Uptake FDG

Mimickers of malignancy• Inflammation• Wound healing, infection, abscesses,

oesophagitis, pancreatitis• Radiotherapy - flare response• Granulomas• TB, sarcoid, histoplasmosis• Miscellaneous

– Paget’s– Graves disease

Combined PET-CT systemsCT PET

Advantages

•Accurate co-registration

•Decrease overall acquisition time

Disadvantages

• radiation – dose by 1/3 (8mSv)

• contrast/breathing artefacts

Diagnosis

Staging

Response

Recurrence or relapse

Imaging in Cancer Diagnosis



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

Left axilla most accessible (also note 8 mm node in pelvis)

Response assessment of treatmentAims 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 undertreatment)

• To spare the patients unnecessary side effects

• To assess residual disease before clinical recurrence

Response to treatment - Burkitts

Staging scan Scan 5 days later post treatment

Breast cancer response assessment



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

Limitations to FDG

• Not readily available in all hospitals• Not taken up in all tumours• High physiological uptake in some areas• Non-specific• Timing in relation to chemotherapy?• Purchasers have limited its use

What other agents are available ?

Other IsotopesCholine11C choline – phospholipid metabolism

• 20 min half life. Less excretion in urine18F Choline – phospholipid metabolism

• 2 hour half life. Excretion in urine



11C Choline

P.V. 66 yo, treated with RT for prostate adk; recentincrease of PSA (10 ng/ml).

11C-CHOLINE 18F-FDG

Courtesy Prof Fanti. Bologna

C-11 choline

Courtesy of Prof FazioMilanStaging

RE-STAGING OF PROSTATE CANCER

67 yo RP 2005 PSA 2 ng/mL

NodesSensitivity 80%Specificity 96%Accuracy 96%

de Jong J Nuc Med 2003

SUSPECT OF RELAPSE C-11 choline

Courtesy of Prof FazioMilan

78 yr oldpsa 4.6ng/mlrestaging



C-11 choline


78 yr oldpsa 4.6ng/mlrestaging


78 yr oldpsa 4.6ng/mllocal recurrence

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• Head & Neck cancers show avid uptake• SUV decreases after 10Gy• SUV reflects the other more complex kinetic

parametersMenda J Nuc Med 2009

18F FLT (fluorothymidine)

• Compared to 18F-FDG

• Lower tumour uptake

• Higher background in liver and marrow

• Not as sensitive in all organs as FDG so not replace it

• Correlated with cell proliferation

• Can indicate response to chemotherapy

• Survival information

Lung cancer• Tumour FDG FLT

• Sensitivity 89-100% 72-100%

• Specificity 86-100% 57-73%

• Nodes - FDG more sensitive than FLT

Salskov. Semin Nuc Med 2007

18F FLT (fluorothymidine)• Head & Neck cancers show avid uptake

• False positives in nodes

• Accurately images tumour during RT

• FDG influenced by inflammatory response

•

Troost J Nuc Med 2010

FLT pre RT

Red=GTVct

FLT post RT 8x2Gy

11C Methionine

• Incorporated into amino acids

• Use for diagnosis of CNS tumours

• Use for suspected recurrence CNS tumours



C11 methionine

C11

FDG

SUSPECT OF RELAPSE

C.R. 44 yo, treated with S + RT for glioblastomaMR inconclusive

11C-METH

18F-FDG

Courtesy Prof FantiBologna

Tumour Hypoxia• Determines• Treatment response• Relapse free survival• Overall prognosis• Resistance to radiotherapy• Mediated by hypoxia inducible factor - HIF-1• Over expressed in cancer cells• Increase mutation rate• Promote gene expression for VEGF

(18F)Fluoromisonidazole (FMISO)

• Assesses hypoxia

• 18F-FMISO enters cells by passive diffusion

• Reduced by nitroreductive enzymes and trapped in

• cells with reduced oxygen

• If oxygen present - parent compound regenerated and metabolites not accumulated

• Accumulates only in viable not necrotic cells

Lee Semin Nuc Med 2007

Lee Semin Nuc Med 2007

Normal distribution

• Metabolised by liver

• Excreted via kidneys

FMISO FDG

Glioma post surgery

DOPA• 18Fluorodihydroxyphenylalinine (18 F-DOPA) – use for neuroendocrine

tumours and phaeochromocytomas. Combined as PET/CT increases sensitivity and specificity

• Most lesions > 2cm detected by CT

• Sensitivity similar to CT at 100% vs 95%

• Specificity better 89% vs 70%

CT PET F-DOPA PET/CT



Staging small NET of the pancreas:

GaDotanoc shows the primary NET

and some secondaryperipancreaticlymph nodes

68Ga – DOTA-NOC

c/o Dr Paolo Castelluci S.OrsolaS.Orsola--Malpighi Hospital, BolognaMalpighi Hospital, Bologna68Ga-DOTATATE scan 18F-FDG scan

Bronchial Carcinoid

68Ga DOTATATE scan

18F-FDG scan

UCL

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 stagingKrabbe Head Neck 2010

FDGC tyrosine

From Krabbe Head Neck 2010

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



PET imaging of cancer related processes

ProliferationFLTAngiogenesisRGD peptides -18F 64Cu, 125I VEGF - 64CuApoptosisAnnexin V – 64Cu, 18FHypoxiaMisonidazole - 18F ATSM - 64Cu

Role of PET- CTClinical

DiagnosisStagingRecurrenceResponse monitoring - PERCIST vs RECIST

DevelopmentalDrug development

labelled drugtracer evaluation of drug effect

Appropriate tracer for biological process



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

2006

2005

I seem to have survived 5 previous requests for future gazing!

2007

2009

Some famous prophesy mistakes!

• “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 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

So beware of prophets!



Whence comes important progress? “Big hit science” versus “incremental development”

• [1] “Big hit science” is the invention or discovery of something so important that the medical world changes for ever because of it. It is what people remember, what reaches the media and what makes some people famous household names. This is rare!

• [2] “Incremental development” is how the vast majority of scientists work. Small parts of a big problem are dissected out and solved.

• Sometimes [2] leads to [1] and often not in any planned way!

1st example of “big hit science”

The invention of x-ray computed tomography

This revolutionised cancer diagnosis

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

Hounsfield’s lab CT scanner 1969

April

1972

press



1st CT scanner (now in Science Museum, London)

Prototype EMI scanner now displayed at Science Museum July 2007 against background of the real Apollo 10 capsure

1994

British stamps are the only ones in the world with no country name as we invented them. Note how CT scanning was so important it made this stamp

1990

This was contoversial! These were the people considered to have “changed the World”. It included politicians, inventors, scientists, humanists but also dictators and media and singing (“pop”) stars.

It included Godfrey Hounsfield

Aug 28th 1919- Aug 12th 2004



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 see this book from IOP Publishing (Bristol (1990)

ISBN 0-85274-305-X

The whole story from 1921 to the 1970s is in my book

2nd example of “big hit science”

The invention of intensity-modulated radiation therapy (IMRT)

This revolutionised cancer treatment by radiotherapy



How IMRT worksThis is actually a movie of a brain treatment but the principle is the same

for prostate or any other organ. You see the 9 modulated beams and the corresponding conformal dose map built up.

How to make a 2D complex modulation by leaf sweep and step-and-shoot with a multileaf collimator (MLC)

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 StraterHotel, Durango, Colorado



In 1993 Thomas Bortfeld and Art Boyer made the first IMRT s-&-s delivery in Houston using a 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)

1993 Bortfeld and Boyer conducted the first multiple-static-field (MSF) experiments using a multileaf collimator (MLC).

0

10

20

30

40

50

60

70

2000 2001 2002 2003 2004 2005 2006 2007 2008

PPN H&N

LUNG PAED

Inverse Planned IMRT TreatmentsThe Royal Marsden (Sutton)

Patient numbers

Planning Systems used: 2000 Corvus; 2001 – 2003, Helax;

2004 – 2008, Philips Pinnacle (DMPO), except Lung: AutoBeam + Pinnacle.

CT based treatment planning increased from 400 to 2100 patients per year over this period. Forward planned, segmental IMRT for breast, prostate and rectum tumour sites in 2008: 150 patients per year.

PPN total 151

H&N 76

Paed 9

Lung (VMAT) 4

Courtesy of Jim Warrington

0

50

100

150

200

250

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Inverse Planned IMRT Treatments dkfz, Heidelberg

Patient number Prostate 154 Lung Cancer/Pleuramesothelioma 98Head and Neck 280 Chordoma/Chondrosarcoma 148Meningeoma 98 Pancreas 91Mamma-Ca 25 Oesophagus-Ca 43others 334

Fluoroscopy to show moving lung / lung tumour

Same patient

Different patient

(courtesy of Helen McNair)

Note the variability of motion. (IMRT research now focuses on motion compensation –IGRT)

Synchronised Delivery

Dr Dualta McQuaid has shown that synchronised leaf tracking can be performed on an Elekta linac

MLC motion

MLC motion

But this IMRT “discovery” alsodid not really come from no-

where. In fact it was the result of decades of “incremental science”

Here are some “precursors”…….



Principle of IMRT in 1940

“IMRT” in 1961

The Royal Free “Tracking Cobalt Unit””.)

The history of IMRT and subsequent

developments are in these 4 books

1993 1997

20002000

20042004

3rd example of “big hit science”(but which came from much

“incremental science”)The invention of emission tomography e.g.

(i) Single photon emission computed tomography (SPECT)

and

(ii) Positron emission tomography (PET)



I guess we wouldn’t stand for this way of reporting today!!

SPECT (almost) in the 1960s and 1970s

PET in the early 1950s, 1960s and 1970s

It is of course much easier to look back and see from where we have comeand to document the big achievements of the past. It is also a proper scientific process. Facts are known! Data are to hand!

Looking to the future is an unscientific process. We are in the realm of hope, expectation, speculation and promise. Nothing is for sure. If it were certain what would happen next we would not be research scientists!

---------------------

So is all lost? No! We can have goals and we can plan the process

Areas in which to work

• Imaging for functional information; SPECT, PET, Magnetic resonance imaging and spectroscopy, Ultrasound and Biomedical optics);

• High-speed digital x-ray and CT imaging; • Need to gain a better understanding of tissue motion on

many timescales;• Radiotherapy for the moving patient not the inert plastic

one;• Focused ultrasound therapy;• Understanding (predicting?) biological response to

therapeutic radiation;• Capitalising on the genome knowledge (how?).• Use of nanoparticles and nanotechnology.

Unusual avenues*….• It is claimed high-intensity, pulsed electric currents

applied to cancer cells can significantly enhance their uptake of cytotoxic drugs.

• the application of photochemical internalization for treating cancer (“Shine the light, release the drug”).

• Biomedical optics may aid cancer screening and molecular imaging.

• Is there a genetic link to late radiation toxicity?• Is there a role for a holographic display system could

help clinicians to develop higher-quality radiation-treatment plans?

* Deduced from a trawl through the IOP Medical Physics Web



Unusual avenues* 2….• Nanotechnology may image contrast agents, become drug

delivery vehicles, act as microsensors and measure locally pH, temperature, drug level, dose, DNA damage?, cell survival?

- E.g. super paramagnetic iron oxide (SPIO) to label cells by transfection

- E.g. Gadolinium as a paramagnetic MRI contrast agent• Quantum dots = nanocrystals of semiconductor material

coated with a shell• Ultrasound microbubbles• The use of microbeams of radiation

*From thoughts of Gerry Battista (Toronto)

health

20 40 60 80 A 100

Age (years)

100% (alive and well and happy) 0% (dead!)

Killed by wild animal

Primitive man

1950s man

2007 man with chronic old age disease

Ideal man

But what is this ideal value A?

Plan for life and death

[1] “Primitive man” may have had no choice. He died young of accidents, malnutrition, poor housing 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 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”….

2009 man with chronic old-age disease

Much progress in cancer research has come (and will continue to come) and will come through

accelerated computer power and storage at lower cost (see next

slides))

Accelerated Exponential Growth

“It is news to no one that the rate of technical change in communications has been accelerating in the past half century. Time to reach 50 M users:

Radio 38 YearsTelevision 16 YearsPC 13 YearsInternet 4 YearsWireless Internet 1 Year

http://www.rice.edu/sallyport/2002/spring/features/president/infotech.html

e+γ(t) t

Data from a slide at ICCR by Gerry Battista

1.2Internet Speed (Mbytes/second)

1 Magnetic Disk Storage(Mbytes per dollar)

2 DRAM Memory (Mbytes per dollar)

0.9 Calculations/Cost Ratio(calculations per second per $1k)

2 Performance/Cost Ratio(MIPS per $1k)

1.8 Microprocessor Instruction Rate Million per s (MIPS)

2 years Moore’s Law

Transistors per microprocessor (Millions)

Doubling Time or

Half Life (Years)

Component

Computer Growth Factors in 2005


Performance/Cost (MIPS per $1,000)

PC-12TP-11

IMRT Plan

Rad-8

3D Plan




Calculations per second per $1,000

1 MFLOP


Research interests

Theory of computation: DNA computing

Discrete mathematics in relation to computer science

Biological Computation: How does biology do information technology?

Biocomputing Laboratory

Awards

1991 for the best mathematics Ph.D. thesis in Finland

Prof Lila Kari Professor & Canada Research Chair in BiocomputingDepartment of Computer ScienceUniversity of Western Ontario London, Ontario Canada N6A 5B7

2002-2011

•In 1 cc DNA is the computing power of all the World’s current computers

•Ten (?) orders of magnitude faster

•Present communication via “ordinary computers”

1 Gbyte per second


“Wish list” to work on for the 3rd Millennium[1] Improving the diagnosis of disease

• 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 summon a doctor when a problem arises;

• 3D multimodality imaging will be routinely requested alongside blood 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[2] Improving the planning of radiotherapy

• Treatment planning will be patient-individualised based on measured radiosensitivity and response to assays and functional imaging;

• Functional and anatomical data will be merged; fuzzy logic may need to be expanded to assign structures to imaging data;

• Tissue contouring will be automatic with minimal human intervention;• By contouring all volumes a database of response versus delivered dose can be

prepared;• Treatment itself will become multimodality with combined photon, proton, ion

therapy merged with brachytherapy, radionuclide therapy and even targetteddrug therapies and focused ultrasound. “Class solutions” will become a thing of the past;

• Multiple plans per patient will be prepared and compared to select the best;• Planning will be 4D with multiple imaging throughout the course of treatment

and re-adjustment of plans to accommodate changed functional status andgeometry;

• Dose calculations will always be by MonteCarlo. All those quaint 20th century terms TAR,TMR,DD etc) will vanish;

• Dose will properly predict biological outcome.

“Wish list” to work on for the 3rd Millennium[3] Improving the delivery of treatment

• All treatment will include truly integrated imaging feedback into the delivery process;

• Before each delivered fraction 3D imaging will inform to reposition the patient accommodating intrafraction daily changes;

• 4D imaging throughout the treatment will guide corrections for intrafractionmotion;

• “Predict ahead” methods will be developed to overcome the latency between gaining information on patient motion and correcting for it;

• C-arm and robotic linacs will deliver dose at a higher fluence rate; flattening filters can vanish and be replaced by modulation;

• Multiple robots (not just one!) will treat the patient just as multiple robots construct cars;

• Every country will have at least one particle accelerator for cancer therapy to act as a National Referral Centre and to gain experience to join the debate;

• Molecular genetics may combine with radiotherapy;• Will microbeam technology be useful?• Can we really hope that heavy ion and proton facilities will be available

worldwide?



“Wish list” to work on for the 3rd Millennium[4] Improving assessing response to treatment

• All patients will have tissue samples taken to enable treatment outcome to be related to biological mechanism;

• All patient dose, treatment outcome, tissue assay data will be stored centrally for future recovery and analysis;

• Patients will fill in patient-specific symptom and response data to refine the biological models of outcome;

• Symptom data and dose data will be brought together to refine the biological models of outcome;

• Post-treatment data collection will be the standard routine practice not the exception. Data will be coordinated through international trials.

“Planning the Process” - What “conditions” are needed for these things to happen?

Medical Physicists need to be:[1] educated at school to find science (which is difficult to do!) rewarding to continue;[2] led to understand that whilst specialising in medical physics is possible, many

medical physics breakthroughs have come from applying the physics from mainstream areas; they need to be studied;

[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”;

[4] allowed to fail and follow blind alleys. Too much grant-driven research will kill the process;

[5] encouraged to avoid repetitive re-invention in medical physics, something all too often seen at conferences;

[6] supported by National and International organisations (with education programmes) 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.

13th Session : winter 2010

A small advertisement if permitted

please:

There are 6 weeks on radiation therapy,

protection, medical imaging and biomedical computing at

this annual Winter School at

Archampsoutside Geneva

www.cur-archamps.fr/esi


Friday 18th June 2010 1

Quality Assurance and Verification for IMRT

Dr Catharine Clark

Contents

• Introduction

• Machine QA

• Patient Specific QA

• Current developments

• Future trends

Introduction

• IMRT is a complex technique

• Requirement for all RT plans to be checked

• Calculations can check TPS, but not delivery

• This talk is about IMRT QA both for the patient plan and for the machine that will deliver it

Key points

• How and why IMRT QA fits into RT workflow

• Comparison of dose distributions– gamma index

• General methods for introduction of complex techniques

• The QA reduction challenge

(IM)RT process

• Immobilisation• Imaging• Volume delineation• Planning• Independent verification• Checking• Transfer to treatment system• Setup• Treatment

(IM)RT process

• Immobilisation• Imaging• Volume delineation• Planning• Independent verification• Checking• Transfer to treatment system• Setup• Treatment



The QA pyramid

1

2

3

4

Basic linac QA

MLC QA

Per patient QA

Set-up

Monthly or other

Monthly

Pre treatment

Daily

The QA pyramid

1

2

3

4

Basic linac QA

MLC QA

Per patient QA

Set-up

Monthly or other

Monthly

Pre treatment

Daily

Machine MLC QA

Dynamic delivery

– Leaf positioning

– Leaf speed

– Leaf stability

– Leaf gap (effect of gravity)

Based on tests by Chui et al. 1996 Med Phys 23(5) 635-641

Dynamic MLC QA

• Leaf positioning

The light field from a static MLC shape is checked against a board with the pattern marked on it which is positioned at isocentre

• Leaf positioning verified at isocentre by light field– Different preset positions

– Varied gantry angles

Dynamic MLC QA

• Leaf Speed test

• 4cm sets of leaves

• A range of gaps

• At varying speeds

• Create different intensities with same dose rate

Dynamic MLC QA



• Leaf Speed test

• An interruption tests the effect of acceleration and deceleration of the leaves on the intensity profile

• Profiles used to check for effects

Dynamic MLC QA

• Leaf Stability: Fence test

• Each bank of leaves moves to predefined positions in the field creating vertical ‘stripes’ of uniform intensity.

• Beam ‘hold’ between control points

• The width of these stripes determines the positional accuracy

Dynamic MLC QA


Dynamic MLC QA


Dynamic MLC QA

• Leaf Gap: gravity

• Tests width of the leaf gap at different gantry angles

• Ratio of dynamic output to open field output is compared

LoSasso et al. Med Phys 28(11), 2209 2001

Dynamic MLC QA Patient specific QA

• Individual fields (often gantry 0º)• Absolute and relative dosimetry

• Accuracy of delivery

• Methods: film, EPID, diode arrays

• Entire treatments (clinical gantry angles)• Absolute and relative dosimetry

• Integrated measurement

• Methods: ion chamber, film, TLD, gel, Monte Carlo



Patient specific QA

• ‘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

Breast IMRT: before treatmentField 1 Field 2

Field 3 Field 4

Patient Image

Cumulative intensity

EPID Verification

1st field 2nd field 3rd field 4th field

EPID images acquired during treatment can be summed to show the integral fluence.

Summed fields

Patient specific QA

• ‘Complex’ IMRT such as prostate or head 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

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?



+ =

Fields delivered with two carriage positions (Varian)

Fade region

0

20

40

60

80

100

120

0 5 10 15 20Position

Inte

nsi

ty

Total

Segment 1Segment 2

• Check that the two sections sum together correctly

• Dose distribution usually verified together

Patient specific QA : Individual fieldsPatient specific QA : Dose

Distributions• Choice of film

• Kodak XOmatV– Lower dose

– Better for individual fields

• Kodak EDR2– Higher dose

– Linear response

– Better for combined fields

Gafchromic EBT film+ Self developing therefore no processing

+ Insensitive to visible light

+ Flatter energy response

- Response dependent on time

- Quite expensive

0

0.1

0.2

0.3

0.4

0 1 2 3

Dose (Gy)

Ne

t O

D

Patient specific QA : Dose Distributions

Coronal plane – verifies all MLC leaves

Transverse plane – easy to compare with TPS


• Diode or ion chamber arrays• Easy to set up

• Quick to read out

• Absolute and relative dose

• Individual fields (clinical angles)

• Resolution of measurement points

2D 3D


• Methods of dose distribution analysis– Profile comparison

– Isodose overlay• Distance to agreement (DTA)

– Dose difference• % difference

– Gamma index• DTA and % dose combined




Profile comparison

Dose difference

TPS

Film


TPS

Film

Isodoseoverlay

Gamma map


• Dose difference not good for high dose gradients

• Better to use distance to agreement (as for penumbra definition)

• Both high and low gradients exist in an IMRT plan

• Gamma index combines dose difference and difference to agreement

• Low et al, Med Phys 25 656, 1998• Depuydt et al, R&O 62(3) 309, 2002

Gamma index

• Forms an ellipsoid of acceptance around each point

• The gamma value at each point is the minimum over all Δr and ΔD

• Typically 3% and 3 mm

• Point is acceptable agreement if < 1

Δr

2

2

2

2

cc ΔD

ΔD

Δr

ΔrD,rγ

toltol

Typical requirement for 95% of the points to have gamma <1, within a given threshold

Gamma index• Geometric

– Easier to align

– Precise construction

– Use with multiple dosimeters

• Anthropomorphic– Inhomogeneities

– Less flexible for measurement points

– Not a model of our patient

Patient specific QA : Phantoms



Patient specific QA : Dose point measurement

• Ion chamber– Instant reading– Everyone has one– Straight forward calibration– Volume averaging– Single point

• TLDs– Multiple points– Factor / readout for each chip– Annealing

• Diode / Ion chamber arrays– Multiple points– Single plane

Patient specific QA : Dose point

• Plan recalculated on a phantom

• No renormalisation– Same leaf motions and MU as for patient

– Doses may be different from patient

• Dose points and distributions compared between calculation on the phantom and delivery to phantom

Patient specific QA : Dose point

• Homogeneous region of dose

• Isocentre may not be the most suitable

• May need to adjust position of the plan on the phantom for measurement point

Summary of initial IMRT QA

• IMRT may require some additional machine QA

• IMRT requires patient-specific QA to test both dose points and dose distribution

• 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 developments

• Portal dose image prediction

• Independent MU calculations

• Back projected portal dosimetry

• Monte Carlo calculations

• Reducing pre-treatment QA

EPID

TPS

Varis

Dosimetric Image

Vis

ion

Vis

ion

TP

S

Fluence map

Portal Dose Prediction

Portal Dose Image Prediction



Portal Dose Image PredictionHead & Neck :

Prostate :

EPID

EPIDPortal Dose Prediction

Portal Dose Prediction

0.6

0.5

0.4

0.3

0.2

0.1

0.0

rela

tive

do

se

-10 -5 0 5 10off_axis position (cm)

PVI PDIP

0.5

0.4

0.3

0.2

0.1

0.0

ab

solu

te d

ose

(G

y)

-6 -4 -2 0 2 4 6

off-axis position (cm)

PVI PDIP

Independent MU calculations

Development: Back projected portal dosimetry

• Backprojected from EPID• Compared with TPS calculated plane• Can be done in phantom or patient• Information about phantom/patient

• Problem in patients as daily changes (eg gas, bladder filling)

• Original CT / daily CBCT

• Actual dose delivered to patient for a particular fraction

Development: Monte Carlo• Currently used in some centres for dosimetryverification along with measurements

• Ease of use increasing with speed of computers and development of interfaces with existing TPS

• Independent MU calculation

• Does not show practical delivery problems

• Differences due to differences in photon algorithms

From Lawrence Livermore National Laboratory

Reducing pre-treatment QA

• For less complex IMRT (prostate)

• Verification by MU calculation and pre-treatment EPID

• Full verification once a month per machine

• Most complex and critical (or new sites) IMRT still verified by measurement

Reducing pre-treatment QA

• More use of independent MU calculations

• Arrays with pre-loaded patient plan

• Greater use of EPID

• Batching of patient QA plans



Future trends

• Expansion of IMRT (30% by 2012 in UK)• Reduction of per patient QA

– Reliance on independent calculation of MU

• Real time delivery verification– Portal imaging– Back projection

• Image guidance, adaptive RT– IMRT must be able to adapt to techniques– Appropriate QA

Key points

• How and why IMRT QA fits into RT workflow

• Comparison of dose distributions– The gamma index

• General methods for introduction of complex techniques

• The QA reduction challenge



Combining Technical Radiotherapy with Chemotherapy and/or Targeted Drugs

Dr Kevin Harrington PhD FRCP FRCR

Reader in Biological Cancer Therapies

Cochrane Shanks/Jalil Travelling ProfessorshipCluj-Napoca, Romania

June 2010

Overview

• Definition of radiosensitivity/radiocurability

• Role of cytotoxic chemotherapy combined with radiation in head and neck cancer

• Rationale for combining targeted drugs with radiation or chemoradiation

• Potential for integrating technical radiation delivery/imaging advances and targeted drugs

• Radioprotection as a clinical strategy

Favourable Tumour

70 Gy 75 Gy

40%

70%

35%

5%

Radiation dose

Pro

bab

ility of tu

mo

ur co

ntro

l (%)

Pro

bab

ility of n

orm

al tissue d

amag

e (%)



Harrington and Nutting, Curr Opin Investig Drugs 2002Tumour dose-response curveNormal tissue dose-response curve

Unfavourable Tumour (1)

Radiation dose (Gy)

Prob

ability of tu

mou

r control

Prob

ability of n

ormal tissu

e dam

age

Complication-free cure

70 Gy 75 Gy

20%

30%

5%

30%

Unfavourable Tumour (2)

5%

Radiation dose (Gy)

Prob

ability of tu

mou

r control

Prob

ability of n

ormal tissu

e dam

age

20%50%

80%

70 Gy 75 Gy

Targeted Dose Escalation

70 Gy 75 Gy

40%

70%

5%

Radiation dose (Gy)

Pro

bab

ility of tu

mo

ur co

ntro

l (%)

Pro

bab

ility of n

orm

al tissue d

amag

e (%)





Radiosensitisation and Radioprotection

Radiosensitisation Radioprotection

Prob

ability of tu

mou

r control

Prob

ability of n

ormal tissu

e dam

age

Radiation dose (Gy)

Nomenclature of Combination Strategies

Radiation

Radiation

Drug

Drug

Induction

Radiation

Drug Drug DrugConcomitant

Adjuvant

Commonly Used Drugs in Chemoradiation

• Cisplatin (CDDP)

• Carboplatin

• Hydroxyurea

• 5-FU/Capecitabine

• Mitomycin C

• Gemcitabine

• Taxanes

Survival Data Subgroup Analyses (1)



Subgroup Analyses (2) Effects of Chemotherapy on Survival at 5 Years: Pignon Meta-Analysis (2000)

Trial Category No. of Trials No. Patients Difference(%) P valueAll trials 65 10850 +4 <0.0001

Adjuvant 8 1854 +1 0.74

Induction 31 5269 +2 0.10PF 15 2487 +5 0.01Other Chemo 16 2782 0 0.91

Concomitant 26 3727 +8 <0.0001

Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002.

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

RANDOMIZE

P

P

F

F

Daily Radiotherapy

Hyperfractionated

EUA

T

Surgery

Progression-Free SurvivalOutcome Data

RANDOMIZE

P

P

F

F

Carboplatin - AUC 1.5 Weekly

Daily Radiotherapy

EUA

T

Surgery

TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

Outcome Data



Post-operative Chemo-RT

60-66 Gy/30-33FCDDP 100 mg/m2 d1, 22, 43

Surgery

228231

60-66 Gy/30-33F

459 pts

66 Gy/33FCDDP 100 mg/m2 d1, 22, 43

Surgery

167167

66 Gy/33F

334 pts

RTOG 9501 Cooper et al NEJM 2004; 350: 1937 EORTC Bernier et al NEJM 2004; 350: 1945

• L-R control HR = 0.61 (95% 0.41-0.91)

• 2-year L-R control = 82% C-RT vs 72% RT

• DFS HR = 0.78 (95% 0.61-0.99)

• OS HR = 0.84 (95% 0.65-1.09)

• 5 year PFS = 47% C-RT vs 36% RT

• OS HR = 0.70 (95% 0.52-0.95)

• 5-year OS = 53% C-RT vs 40% RT

Why Combine Radiation and New Agents?

Doublings Cells Mass• Radiation frequently fails to kill all clonogens

• New targeted drugs unlikely to be effective stand-alone therapies

• Smart targeting offers the prospect of mechanistically favourable combinations

• Opportunities for additive, synergistic and independent activities

• Toxicities may not overlap

Rationale for Targeted Therapy plus RT

• Overcome resistance mechanisms (non-cross resistance)

• Spatial co-operation

• Radiosensitisation

• Favourable alteration of tumour biology

– Reoxygenation

– Cell cycle redistribution

– Inhibit DNA repair

– Impair (accelerated) repopulation

Target Selection

Cell cycle targetingTelomerase targeting

Hypoxia targetingAnti-VEGF targeting

Anti-invasive agents (MMP)Chemokine blockade

p53 targetingTRAIL

Anti-bcl2

Growth factor receptor targetingSignal transduction pathway targeting

Restoration of growth arrest

Cetuximab Plus RT

Bonner et al. NEJM 2006; 354: 567 0 2 4 6 8 10 12

Dose (Gy)

0.001

0.01

0.1

1

Su

rviv

ing

fra

ctio

n

SC69

U2

SQD9

A549

A1847

SCC61

MCF7

Biological Contributors to Outcome

HYPOXIA REPOPULATION

INTRINSICRADIOSENSITIVITY



Tumor Hypoxia?

RapidProliferation ?

IntrinsicResistance ?

Critical Molecular Target?

Rapid Proliferation

Accelerated Radiotherapy

Hypofractionation

Concomitant Chemo-RT

EGFR blockade

Acute

Increase oxygenation:Vasoactive drugs (e.g. Nicotinamide)

Chronic Hypoxia

Increase oxygenation:OxygenHypoxic sensitizer

(e.g. Nimorazole)

Target Hypoxia:Hypoxic cytotoxins (TPZ)Gene therapyBiological response (e.g. inhibit HIF-1)IMRT Boosts

High DNA repair

Inhibit DNA RepairChemotherapyGene therapyInhibitor of DNA repair

Increase DNA damage:RadiosensitizerHyper/ultrafractionationDose escalation (3-DCRT, IMRT, stereotaxy, isotope) Concomitant chemotherapy

Biological tumor identity card (proteo-genomic )

Integrators of upstream response?p53: gene therapy, p53 specific drugsmTOR: RapamycinHSP90: GeldanamycinProteasome inhibitor

Single molecular target?bcr-abl: ImatinibRas activation: FTIEGFR: EGFR blockade

Genotype

Phenotype

Guiding Use of Radiotherapy and Targeted Therapy Integration of New Technology and New Biology

• New Technology– Molecular imaging (pCT, DCE-MRI, PET)

– 3-D conformal RT

– Intensity-modulated RT

– Image-guided RT

– Adaptive radiotherapy

– New targeted radioisotope therapies

• New Biology– Tumour profiling

– Response prediction

– New therapeutics

MRI/CT fusion

Geographical miss Radioresistance

PET/CT DCE-MRI, DW MRI,

Perfusion CT

FUNCTIONALANATOMICAL

Anatomical vs Functional Imaging

Body outline

Gross TumourVolume

BTV

Body outline

BTV

GTV

Avoidance of Geographical Miss Delivery of Boost to Radioresistant Volume

Biological Target Volumes

Interactions of Chemotherapy and Radiotherapy• Platins

– Formation of toxic platinum intermediates in the presence of ROS– Radiation-induced increased cellular uptake of platin– Inhibition of DNA repair– Cell cycle arrest

• 5-FU– Killing of radiation resistant cells in S phase– Radiation induced expression of thymidine phosphorylase in

cancers

• Gemcitabine (hydroxyurea)– Depletion of dNTP pools– Inhibition of ribonucleotide reductase

Improved Use of RT as an Executor Function

Normal tissue sparing

Tumour dose escalation

RT Boost to Biologically Relevant Populations

Addition of Targeted

Agents

Imaging

• Proliferation

• Hypoxia

• Apoptosis

• Oncogenedependence



Radioprotection

Radioprotection

Prob

ability of tu

mou

r control

Prob

ability of n

ormal tissu

e dam

age

Radiation dose (Gy)

• Approach arose from work in 1950s to improve battlefield capability in nuclear war

• Aim to spare dose-limiting tissues from radiotoxicity

• Prototype compounds include WR2721

• Concerns about protection of cancer cells

• Clinical studies focussed on mucositis, xerostomia

Amifostine: Clinical Experience

• 315 patients

• RT 50-70 Gy at 1.8-2.0 Gy per day (radical or adjuvant)

• 75% of both parotid glands in RT high-dose volume

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

• Open-label

Amifostine: Clinical Experience

• BUT … read Brizel DM, Overgaard J. Lancet Oncol. 2003; 4: 378.

rhKGF: Clinical Experience

Spielberger et al NEJM 2004

rhKGF: Clinical Experience

Spielberger et al NEJM 2004

• 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



Toxicity Endpoints

• No significant benefit from rhKGF• No effect on PFS/OS

IMRT – Reducing the dose to the parotid gland in tonsil cancer

Conventional radiotherapy parallel

opposed fields

IMRT sparing left parotid

Endpoints

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, pattern of recurrence

– Quantitative saliva flow measurements

– Quality of Life

* partial but persistent or complete dryness

p=0.004

74

39

3 6 12

Months post treatment

Percentage≥G2

CRT IMRT

n=34

n=38

p=0.04 p=0.01

8386

62 60

n=36

n=45

n=40

n=45

18

p=0.003

71

29

n=21

n=31

LENT SOM Subjective Xerostomia* rates

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



Head and Neck IMRT Evidence Base

Dr Christopher M Nutting MD FRCP FRCRConsultant and Reader in Clinical Oncology,

Clinical Director, Head and Neck Unit, Royal Marsden Hospital & Institute of Cancer Research, Fulham Road,

London

Better targeting of radiotherapy is required

1. To reduce radiotherapy complications and improve quality of life for head and neck patients

2. To deliver higher doses of radiation to improve local or 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 radiotherapy

1. Intensity Modulated Radiotherapy (IMRT)

2. Image Guided Radiotherapy (IGRT)

3. Stereotactic Body Radiotherapy (SBRT)

What is IMRT?

Tumour

TissueConventional Radiotherapy

Intensity Modulated Radiotherapy

Dose

Clinical examplesHead 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



Goals of RMH H&N IMRT Program

1. Reduce toxicity by improved dose distributions to OAR

Site: Oropharynx – Parotid gland sparing

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






First Results of a Phase III Multi-Centre Randomised Controlled Trial of Intensity

Modulated vs Conventional Radiotherapy in Head and Neck Cancer:

PARSPORT (CRUK/03/005)

C. Nutting, R. A'Hern, M. S. Rogers, M. A. Sydenham, F. Adab,

K. Harrington, S. Jefferies, C. Scrase, B. K. Yap, E. Hall,

on behalf of the PARSPORT Trial Management Group

PARSPORT

Background (1)

• Radiotherapy for head and neck cancer is frequently curative, but at a price of significant long term side effects

• Xerostomia is the most prevalent late radiation toxicity of radiotherapy to the head and neck region

• Xerostomia leads to reduced speech and swallow function, accelerated dental caries and osteoradionecrosis

Nutting et al Proc ASCO JCO 2009;27(2):799s

Background (2)

• Intensity-modulated radiotherapy (IMRT) produces complex dose distributions which can reduce the dose to salivary glands

• Phase II data suggests that parotid-gland sparing IMRT maintains saliva production

• PARSPORT is a phase III randomised trial to test this hypothesis

• PARSPORT is the only randomised trial of IMRT in SCCHN


Conventional radiotherapy (CRT)

Head and neck cancer patientsat risk of radiation induced xerostomia

(oropharynx/hypopharynx)

Randomisation 1:1

Parotid-sparing IMRT

PARSPORT Trial Design

65Gy/30 fractions in 6 weeks - radical and post-operative R1/R260Gy/30 fractions in 6 weeks - post-operative R0




Principal Inclusion Criteria

• Histologically confirmed SCCHN

• Oropharynx or hypopharynx (T1-4 N0-3 M0)

• High risk of xerostomia (i.e. estimated mean dose to both parotid glands >26Gy)

• Primary or post-operative radiotherapy

• WHO performance status 0-1

• Neo-adjuvant chemotherapy was allowed


Radiotherapy Planning and QA

• PARSPORT was the first multi-centre head and neck IMRT trial in the UK

• Detailed, rigorous, centralised QA program was established

• Each centre had to submit specimen target volume definition and radiotherapy plans for approval prior to recruiting patients*

• 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 in tonsil cancer

Conventional radiotherapy parallel

opposed fields

IMRT sparing left parotid


Endpoints

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– Quantitative saliva flow measurements– Quality of Life


Patient and Tumour Characteristics

31.9 (23.6-38.8)Median follow-up (IQR) months

23%77%

AJCC stage I/II (T1/2, N0, M0)AJCC stage III/IV (T3/4, N1-3)

85%15%

Site: OropharynxHypopharynx

58.4 (37.5-82.8)Mean Age (Range) years

72%Male

94Number randomised


Treatment Received

2019 40% 43%Received neoadjuvant chemotherapy

81%3862%29Radiotherapy given as radical treatment

(0.4)

(10.6)

(6.8)

65 Gy

45 Gy

26 Gy

(0.5)

(6.3)

(6.5)

65 Gy

59 Gy

60 Gy

Mean (SD) radiotherapy dose PTV1

Ipsilateral Parotid mean (SD) dose

Contralateral Parotid mean (SD) dose

(2.2)

(12.9)

(3.7)

61 Gy

50 Gy

27 Gy

(2.3)

(5.0)

(10.3)

64 Gy

61 Gy

57 Gy

Mean (SD) radiotherapy dose PTV1

Ipsilateral Parotid mean (SD) dose

Contralateral Parotid mean (SD) dose

815 32% 17%Radiotherapy given post-operatively

46†43* 91% 98%Radiotherapy delivery as per protocol

IMRT n=47CRT n=47

* 1 received IMRT due to coverage; 1 ineligible; 2 refused;† 1 deviated due to rectal bleed




Incidence of ≥G2 Acute Toxicity*

0.0587%98%Dysphagia

0.1891%98%Mucositis clinical

0.0380%95%Salivary gland

0.1176%89%Pain

0.0271%91%Dry mouth

0.2329%18%Hair loss

0.3244%34%Weight loss

<0.0176%41%Fatigue

0.1373%86%Mucositis functional

0.0276%93%Rash

p(chi-squared)

IMRT n=45

CRTn=44

Toxicity(Graded according to CTCAE v3)

*during and up to 8 weeks post RT* partial but persistent or complete dryness

LENT SOM Subjective Xerostomia* rates

p=0.004

74

39

3 6 12Months post treatment

Percentage≥G2

n=34

n=38

p=0.04 p=0.01

8386

62 60

n=36

n=45

n=40

n=45

18

p=0.003

71

29

n=21

n=31

CRT

IMRT

3 6 12 18

CRT

IMRT

Months post treatment

Percentage ≥G2

p=0.03 p=0.001 p=0.05 P<0.001

RTOG Subjective Salivary Gland toxicity ≥G2*

78

56

83

47

64

41

81

20

n=41

n=45

n=36

n=45

n=33

n=37

n=21

n=30

*Moderate or complete dryness of mouth poor or no response on stimulation

Incidence of LENT SOM ≥ G2 at 12 months

0.5523%15%Mucosa

0.468%15%Skin

1.003%0%Spinal cord

0.505%0%Larynx

0.470%3%Ear

0.593%6%Teeth

0.4413%6%Oesophagus

1.0013%12%Mandible

p (exact)IMRT(n=39)

CRT(n=34)

Toxicity

Incidence of RTOG ≥G2 at 12 months

0.708%12%Mucous membranes

1.003%3%Bone

1.006%3%Skin

0.593%6%Joint

-0%0%Larynx

1.005%6%Subcutaneous tissue

0%

10%

IMRT(n=37)

-0%Spinal cord

0.373%Oesophagus

p (exact)CRT(n=33)

Toxicity


Overall Survival

5/342/451/470/47IMRT

3/323/401/440/47CRT

n events/at risk

0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18

Months from end of treatment

Pro

po

rtio

n a

live

1 year overall survival (95% CI):

CRT (n=47): 90.8% (77.3 – 96.4)

IMRT (n=47): 93.6% (81.5 – 97.9)

CRT

IMRT

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




0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18

Pro

po

rtio

n p

rog

ress

ion

fre

e

Loco-Regional Progression Free Survival (LRPFS)

6/304/412/460/47IMRT

2/285/360/450/47CRT

Months from end of treatmentn events/at risk

1 year LRPFS (95% CI):

CRT (n=47): 88.0% (73.5 – 94.8)

IMRT (n=47): 87.3% (73.9 – 94.1)

CRT

IMRT

Hazard Ratio (IMRT:CRT) = 1.59 (0.67 to 3.80)


Conclusions

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

• Acute radiation fatigue was more prevalent with IMRT possibly due to more normal tissue irradiation

• Further follow-up is required to determine the maximum benefit of this technology

• These data support the adoption of IMRT as the standard of care for head and neck cancer patients


Nasopharynx: parotid gland sparing IMRT

• Pow et al IJROBP 2006

• Small randomised trial of 51 patients with T2 N0/1 M0 nasopharynx cancer: CRT vs IMRT

• Stimulated and unstimulated saliva flow was greater in IMRT patients starting 2 months after treatment and increasing over time (p=0.002)

• Recovery of parotid flow to at least 25% of pre-treatment levels was 83% with IMRT, and 10% with CRT

• QoL domains tested with QLQ 30 and HN35 over initial 12 months

Nasopharynx: parotid gland sparing IMRT

• QoL reduced between baseline and 2 months, then increased similarly over time in both groups (NS)

• HN35: IMRT patients had improved dry mouth swallowing and sticky saliva scores (p≤0.01)

• No correlation was seen between saliva flow rates and QoL

• HN35: Saliva flow rate did correlate with speech, dry mouth, and sticky saliva domains

Pow et al IJROBP 2006






Updated Results of Phase I/II Dose Escalation Trial of Chemo-IMRT in

Advanced Laryngopharyngeal Cancer



Typical approach for locally advanced Larynx/Hypopharynx

PTV1: Gross primary tumour ± involved nodes = Radical Dose of 70Gy 35F

PTV2: Elective nodal areas = Elective dose of 50Gy 25F

Conventional vs IMRT

Represents approx 50% reduction of vol of tissue irradiated to radical dose

RMH Dose escalation trial Doses

50Gy 25# (2Gy)N/A

70Gy 35# (2Gy)BED10Gy 74.1, BED3Gy 116.67Log cell kill 10.26

Conventional 70Gy 35#

56Gy 28# (2.0Gy)N/A

67.2Gy 28# (2.4Gy)BED10Gy 72.8, BED3Gy 121.0Log cell kill 11.06

Dose level 2

52Gy 28# (1.85Gy)N/A

63.0Gy 28# (2.25Gy)BED10Gy 66.6, BED3Gy 110.3Log cell kill 10.12

Dose level 1

PTV 2PTV 1

Fowler 2009: Work in progress

Inhomogeneous IMRT dose distribution: theoretical risks and benefits

1.85Gy/# 2.25Gy/# x28#

Dose 51.8 and 63.0 Gy

•High total dose (D)

•Acceleration with hypo-

fractionation to primary: Care

with low α:β OAR in PTV 1

•Low fractionation sensitivity

of microscopic disease

•Single-phase plan for 28F

•10-15 minutes to deliver

•No electrons

Phase I/II Trial Design

• n = 15 for each dose level initially, expanding to 30

•Main expected toxicities were Late: cartilage necrosis, oesophageal stricture

•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

Induction and Concomitant Chemotherapy

IMRT 28 #

Induction chemotherapy

Cisplatin 80/m2 d1

5FU 1000mg/m2 d2-5

Ind 1 Ind 2

Concomitant Chemotherapy

Cisplatin 100/m2 d1 + 28

Carboplatin AUC 5 substituted if Cisplatin contraindicated

Bhide et al BJC 2008



Mean treatment time:

•63.0Gy cohort: 393 days•67.2Gy cohort: 381 days

NO TREATMENT BREAKS

97-100% COMPLIANCE WITH INDUCTION +

COMCOMITANT CHEMOTHERAPY

Results: Demographics

Guerrero Urbano et al 2008

97%3%

83%17%

PS01

00

16150

11

12132

IIIIIIIVAIVB

1615

1712

LarynxHypopharynx

6358Median Age

77%79%Male

36 (17-62)49 (35-78Median Follow up (months)

3129Number

Dose level 2Dose level 1

ACUTE RADIATIONDERMATITIS

0.0%

25.0%

50.0%

75.0%

100.0%

1 2 3 4 5 6 7 8 9 10 14

G3 63.0Gy

G3 67.2Gy

G2 63.0Gy

G2 67.2Gy

Guerrero-Urbano 2008 R&O

RADIATION INDUCED DYSPHAGIA

63.0Gy cohort: Spearman’s rank correlation coefficient between mucositis and dysphagia

0.6 (p=0.02)

Prevalence of acute G3 dysphagia

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

1 2 3 4 5 6 7 8 9 10 14

Follow-up (weeks)

G3

dysp

hagi

a, %

67.2Gy cohort

63.0Gy cohort


ACUTE TOXICITY: NCI CTC v.2.0 scale

Incidence of acute G2 and G3 toxicity

63.0Gy cohort 67.2Gy cohort

G2 G3 G2 G3

Dermatitis 66.7% 20% 46.7% 20%

Mucositis 33.3% 66.7% 46.7% 40%

Dysphagia 20% 66.7% 13.3% 86.7%

Pain 46.7% 26.7% 53.3% 40%

Xerostomia 60% 0 73.3% 6.7%


0%0%30% (7)0%0%43% (9)Mucosa

0%0%12% (3)0%5% (1)19% (3)Skin

0%7% (2)30% (7)0%0%14% (3)Subcutaneous

0%7% (4)58% (14)0%24% (5)33% (7)Larynx

0%8% (2)54% (9)0%9% (2)43% (9)Salivary Gland

8% (3)29% (7)60% (15)5% (1)0%25% (5)Oesophagus

Grade ≥III

Grade II

Grade I

Grade ≥ III

Grade II

Grade I

Organ

Dose Level II (67.2 Gy/28 #)Dose Level I (63 Gy/28 #)

Late Normal Tissue Toxicity at 1 yearDose escalation trial results at 2 years

74%72%Overall survival

96%89%Larynx preservation rate

78%62%DFS

78%64%Loco-regional PFS

82%68%Loco-regional control

86%71%Local control

36M51MMedian Follow up

DL2DL1



Outcome: SurvivalSurvival Function

Time to death- months

483624120

Cu

m S

urv

iva

l

1.0

.8

.5

.3

0.0

Survival Function

Censored

Overall Larynx preservation rate 89 vs 96% at 2 years

Loco-regional 68% vs. 82% at 3 years

group01

event_lr

0 10 20 30 40 50 60 70

100

90

80

70

60

50

40

30

20

10

0

Time

Su

rviv

al p

rob

ab

ility

(%

)

Number at riskGroup: 0

29 25 16 10 7 5 2 1Group: 1

31 24 13 10 7 0 0 0

Other dose escalation results

• Madani et al IJROBP 2007;68(1) 126-35– Dose escalated PET+ve regions– 72.5Gy and 77.5Gy in 32 fractions– High levels of local control were seen– 2/18 in DL2 had G4 toxicity, 1/18 fatality– We are close to the dose which may cause fatal

mucosal necrosis– Reductions to the GTV are probably needed to

deliver such high doses– Patients should be treated within the context of

clinical trials.

Proposed Phase III Trial Schema

Induction chemotherapy [Optional by centre]

CONSENT

Male or female

patients aged 18-70 with

locally advanced

squamous cell cancers of the

larynx or hypopharynx

requiring definitive

treatment with chemo-

radiotherapy

Complete baseline Quality of

Life

Radiotherapy - Experimental Arm

67.2Gy in 28 fractions to the involved site and nodal groups56Gy in 28 fractions to nodal areas at risk of harbouring microscopic disease.

Radiotherapy - Conventional Arm

65Gy in 30 fractions to involved site and nodal groups54 Gy in 30 fractions to nodal areas at risk of harbouring microscopic disease.

Patients may receive a maximum of 3 (21 day) cycles of platinum based induction chemotherapy prior to radiotherapy

All patients will receive concomitant platinum 100mg/m2 on day 1 & 29 of their RT schedule

R

Conclusions

• Dose escalation with IMRT is possible at the expense of increased acute toxicity

• Late radiation toxicity at 1-3 years is not enhanced and is similar to reported contemporary series

• Significant increases in local tumour control are seen in this small phase II trial

• A randomised trial is proposed by the H&N IMRT group and will open Q3 2010

Targeting with PETCT

CT alone PET alone PETCT

Newbold et al 2008 Daisne et al, Radiology 2004

• Comparison of CT, MRI and FDG-PET with surgical specimen

• FDG-PET closest to pathology



• Hypoxia confers radiation resistance on cancer cells

• Hypoxia represents a potential target for radiation dose intensification

• Several techniques potentially allow imaging of hypoxia for radiation targeting

• DCE-MRI, dCT, CuATSM, Misoonidazole

Targeting hypoxia with DCE-MRIValidation of DCE-MRI with hypoxia staining

• Pimonidazole fixation and CA9 expression were detected using an IHC technique

• Path section matched to image slice

• ROIs transferred between path and images

DCE-MRI

Newbold et al 2008

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



Common pitfalls in head and Common pitfalls in head and neck cancer imagingneck cancer imaging


BirminghamBirminghamUKUK

ESH


Pitfalls Pitfalls

TechniqueTechnique Benign diseaseBenign disease Large volume diseaseLarge volume disease Post treatmentPost treatment

Radiotherapy changeRadiotherapy change Appearances post surgeryAppearances post surgery

Recurrent diseaseRecurrent disease Nodal diseaseNodal disease

Technique Technique CTCT Larynx Larynx -- angle or reconstruct parallel to vocal angle or reconstruct parallel to vocal

cordscords Gentle respirationGentle respiration No swallowingNo swallowingMRIMRI Choice of sequenceChoice of sequence––eg.dessicatedeg.dessicated secretions, secretions,

slow flowing blood, blooming from slow flowing blood, blooming from parapara--magnetic substances on GE sequencesmagnetic substances on GE sequences

Use of faster sequences Use of faster sequences egeg BLADE for motion BLADE for motion artefactartefact

Communication with clinicianCommunication with clinician

Do not presume that every lesion is Do not presume that every lesion is malignant malignant –– communication importantcommunication important

Post biopsy changePost biopsy change Vocal cord stripping for Vocal cord stripping for dysplasiadysplasia

Large volume diseaseLarge volume disease

May May prolapseprolapse into/obliterate into/obliterate hypopharynxhypopharynxsimulating invasionsimulating invasion

Would alter surgeryWould alter surgery Usually not a problem Usually not a problem -- endoscopyendoscopy

Post radiotherapy changePost radiotherapy change symmetric thickening of the epiglottis, symmetric thickening of the epiglottis,

aryary--epiglotticepiglottic folds and false cords folds and false cords ––within 3 months of completionwithin 3 months of completion

posterior pharyngeal wall thickens and posterior pharyngeal wall thickens and mucosa enhancesmucosa enhances

retropharyngeal space oedemaretropharyngeal space oedema increased attenuation of increased attenuation of paralaryngealparalaryngeal

fat fat -- within 2 monthswithin 2 months Symmetric thickening of Symmetric thickening of subglotticsubglottic fat fat

seen in 80%seen in 80% thickening of anterior and posterior thickening of anterior and posterior

commissurescommissures-- late changes 7late changes 7--14 months14 months

Mukherji and Weadock EJR2002;44:108



Surgery Surgery Post biopsyPost biopsy TracheostomyTracheostomy Treatment of primary tumourTreatment of primary tumour

Partial and total Partial and total laryngectomylaryngectomy KelschKelsch and Patel Seminars in Ultrasound, CT and Patel Seminars in Ultrasound, CT

and MRI 2003;24:147and MRI 2003;24:147--156156

Small bowel interpositionSmall bowel interposition Surgical flaps Surgical flaps

WesterWester et al AJR 1995;164:989et al AJR 1995;164:989--9393

SurgicelSurgicel

Post Post tracheostomytracheostomy

Swelling and surgical emphysema will Swelling and surgical emphysema will distort soft tissuesdistort soft tissues

Beware Beware overstagingoverstaging subglotticsubglottic extensionextension SubglotticSubglottic tissue should be in continuity with tissue should be in continuity with

tumourtumour CricoidCricoid cartilage involvementcartilage involvement

Total Total laryngectomylaryngectomy

Loss of thyroid and Loss of thyroid and cricoidcricoid cartilages and cartilages and hyoid bonehyoid bone

Oesophagus has rounder configurationOesophagus has rounder configuration--walls 2walls 2--3mms thickness3mms thickness

Variable resection of thyroid Variable resection of thyroid –– remaining remaining May be mistaken for recurrenceMay be mistaken for recurrence

Surgery Surgery –– treatment and staging of treatment and staging of nodal disease nodal disease -- Neck dissectionNeck dissection

Asymmetry/absence of the Asymmetry/absence of the submandibularsubmandibularglandgland May give rise to May give rise to ““palpable masspalpable mass”” and may be and may be

interpreted as disease by radiologist!interpreted as disease by radiologist! Lack of fat plane around the vascular Lack of fat plane around the vascular

compartmentcompartment DenervationDenervation of the accessory (shoulder of the accessory (shoulder

dysfunction) and hypoglossal nervesdysfunction) and hypoglossal nerves

DenervationDenervation following neck following neck dissectiondissection

22/174 patients following RND abnormal 22/174 patients following RND abnormal and/or and/or hemiatrophyhemiatrophy on the side of the on the side of the tongue operated ontongue operated on

No evidence of tumour recurrence and no No evidence of tumour recurrence and no evidence of soft tissue recurrence along evidence of soft tissue recurrence along course of hypoglossal nerve.course of hypoglossal nerve.

Murakami et al AJNR 1998;19:515

FlapsFlaps

Knowledge of appearance of flapsKnowledge of appearance of flaps Nodes within flapsNodes within flaps DenervationDenervation of flapsof flaps-- abnormal abnormal

enhancement may be mistaken for enhancement may be mistaken for recurrent diseaserecurrent disease



Foreign bodiesForeign bodies

ClipsClips ThyroplastyThyroplasty –– treatment of vocal cord treatment of vocal cord

paresisparesis TeflonTeflon GortexGortex SilasticSilastic

Recurrent diseaseRecurrent disease

CartilageCartilage Sclerotic foci are more likely to represent reaction to Sclerotic foci are more likely to represent reaction to

surgery. Obvious cartilage destruction by a soft tissue surgery. Obvious cartilage destruction by a soft tissue mass = tumourmass = tumour

Soft tissue massSoft tissue mass Mass> 10mm have 63% probability of being Mass> 10mm have 63% probability of being

malignant. (malignant. (MaroldiMaroldi et al). Soft tissue thickening et al). Soft tissue thickening >1mm at anterior >1mm at anterior commissurecommissure suspicious, but beware suspicious, but beware post radiotherapy change and post op post radiotherapy change and post op granulomagranuloma!!

Neck nodesNeck nodes

Central necrosis Central necrosis –– pitfallspitfalls Fatty Fatty hilarhilar metaplasiametaplasia

Usually at periphery of nodeUsually at periphery of node If central may be indistinguishable from If central may be indistinguishable from

necrotic malignant nodenecrotic malignant node Usually in response to chronic nodal infectionUsually in response to chronic nodal infection

ThrombosedThrombosed IJVIJV Other mimicsOther mimics

ConclusionConclusion

Ensure good techniqueEnsure good technique Good clinical historyGood clinical history Image before interventionImage before intervention Radiologists and clinicians need to work Radiologists and clinicians need to work

very closely togethervery closely together

head and neck conformal therapy and imrt course

Documents