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
2
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
3
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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Personal profile of the lecturers
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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Personal profile of the lecturers
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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Personal profile of the lecturers
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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Personal profile of the lecturers
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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Personal profile of the lecturers
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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Personal profile of the lecturers
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?
Day 1 Session 1 Lecture 19:15am
2Wednesday 16th June 2010
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.
Day 1 Session 1 Lecture 19:15am
3Wednesday 16th June 2010
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.
Day 1 Session 1 Lecture 19:15am
4Wednesday 16th June 2010
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
Day 1 Session 1 Lecture 19:15am
5Wednesday 16th June 2010
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.
Day 1 Session 1 Lecture 19:15am
6Wednesday 16th June 2010
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)
Day 1 Session 1 Lecture 19:15am
7Wednesday 16th June 2010
(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
Day 1 Session 1 Lecture 19:15am
8Wednesday 16th June 2010
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
Day 1 Session 1 Lecture 19:15am
9Wednesday 16th June 2010
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
Day 1 Session 1 Lecture 19:15am
10Wednesday 16th June 2010
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
Day 1 Session 1 Lecture 210:00am
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 2
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 3
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 4
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 5
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 6
Mould roomMould room
Immobilisation shell Simulation
Treatment planning Radiotherapy planning
•Define field borders
•Outline through centre of volume
•Define treatment volume
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 7
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 8
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 9
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 10
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
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 11
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
Level V: Cranial edge hyoid bone to Transverse cervical vessels
Post edge SCM
Platysm
a
anterior edge trapezius m.
PSm
PSm
Pla
tysm
a
Day 1 Session 1 Lecture 210:00am
Wednesday 16th June 2010 12
Level V: Cranial edge hyoid bone to Transverse cervical vessels
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
PRIMARY TUMOUR OUTLINING
• 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!
Day 1 Session 1 Lecture 310:45am
Wednesday 16th June 2010 1
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
Day 1 Session 1 Lecture 310:45am
Wednesday 16th June 2010 2
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
Day 1 Session 1 Lecture 310:45am
Wednesday 16th June 2010 3
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
Day 1 Session 1 Lecture 310:45am
Wednesday 16th June 2010 4
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
Day 1 Session 1 Lecture 310:45am
Wednesday 16th June 2010 5
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
Day 1 Session 2 Lecture 411:45am
Wednesday 16th June 2010 1
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
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP
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
Day 1 Session 2 Lecture 411:45am
Wednesday 16th June 2010 2
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
Laryngeal cartilage invasionLaryngeal cartilage 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
Laryngeal cartilage invasionLaryngeal cartilage invasion
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
Day 1 Session 2 Lecture 411:45am
Wednesday 16th June 2010 3
Laryngeal cartilage invasionLaryngeal cartilage invasion
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
Becker M Radiology 2008; 249:551
Inflammation of thyroid cartilage
Becker M Radiology 2008; 249:551
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
Day 1 Session 2 Lecture 411:45am
Wednesday 16th June 2010 4
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
Day 1 Session 2 Lecture 411:45am
Wednesday 16th June 2010 5
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
Wednesday 16th June 2010 1
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
Define clinical dose specificationsDefine clinical dose specifications
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
Define clinical dose specificationsDefine clinical dose specifications
Including all volumes of (any) interest
full 3D outlining of the volumes
Delineate contoursDelineate contours
Day 1 Session 2 Lecture 512:30pm
Wednesday 16th June 2010 2
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
Selecting beam parametersSelecting beam parameters
• 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
Selecting beam parametersSelecting beam parameters
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 !!
Optimisation parametersOptimisation parameters
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
Optimisation parametersOptimisation parameters
Day 1 Session 2 Lecture 512:30pm
Wednesday 16th June 2010 3
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
Day 1 Session 2 Lecture 512:30pm
Wednesday 16th June 2010 4
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
Day 1 Session 2 Lecture 512:30pm
Wednesday 16th June 2010 5
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
Wednesday 16th June 2010 1
The The parapharyngealparapharyngeal spacespace
Julie OlliffJulie OlliffUniversity HospitalUniversity Hospital
Birmingham Birmingham UKUK
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 2
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 3
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)
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 4
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 1
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 2
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 3
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 4
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 5
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%)
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 6
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 7
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 8
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 9
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
Day 1 Session 3 Practical Session2:00pm
Wednesday 16th June 2010 10
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
Day 1 Session 3 Lecture 64:00pm
Wednesday 16th June 2010 1
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
?
Day 1 Session 3 Lecture 64:00pm
Wednesday 16th June 2010 2
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
Day 1 Session 3 Lecture 64:00pm
Wednesday 16th June 2010 3
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
Day 1 Session 3 Lecture 64:00pm
Wednesday 16th June 2010 4
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
Day 1 Session 3 Lecture 64:00pm
Wednesday 16th June 2010 5
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
Day 1 Session 3 Lecture 64:00pm
Wednesday 16th June 2010 6
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)
Day 1 Session 3 Lecture 64:00pm
Wednesday 16th June 2010 7
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
Day 1 Session 3 Lecture 64:00pm
Wednesday 16th June 2010 8
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
Day 2 Session 1 Lecture 79:00am
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
2. PRIMARY TUMOUR OUTLINING
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
Day 2 Session 1 Lecture 79:00am
Thursday 17th June 2010 2
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
Day 2 Session 1 Lecture 79:00am
Thursday 17th June 2010 3
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
Day 2 Session 1 Lecture 79:00am
Thursday 17th June 2010 4
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
Level V: Cranial edge hyoid bone to Transverse cervical vessels
Post edge SCM
Platysm
a
anterior edge trapezius m.
PSm
PSm
Pla
tysm
a
Level V: Cranial edge hyoid bone to Transverse cervical vessels
Post edge SCM
anterior edge trapezius muscle
PSm
Pla
tysm
a
Day 2 Session 1 Lecture 79:00am
Thursday 17th June 2010 5
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
2. PRIMARY TUMOUR OUTLINING
PRIMARY TUMOUR OUTLINING
• NO ACCEPTED GUIDELINES
• Sources of information:– Tumour site/ stage
– Tumour natural history
– Anatomical descriptions
– Surgical experience
– Lessons from conventional radiotherapy
Day 2 Session 1 Lecture 79:00am
Thursday 17th June 2010 6
PRIMARY TUMOUR OUTLINING
• 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
Day 2 Session 1 Lecture 79:00am
Thursday 17th June 2010 7
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
Day 2 Session 1 Lecture 79:00am
Thursday 17th June 2010 8
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
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 1
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
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 2
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
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 3
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
Indications• Primary extent of tumour• Nodal staging. • Metastases• Treatment planning• Response to treatment – post CRT• Recurrence• Unknown primary
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 4
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
FDG-PET in Head & neck cancer
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
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 5
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
FDG-PET in Head & neck cancer
Indications• Primary extent of tumour• Nodal staging. • Metastases• Treatment planning• Response to treatment – post CRT• Recurrence• Unknown primary
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
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 6
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
FDG-PET in Head & neck cancer
Indications• Primary extent of tumour• Nodal staging. • Metastases• Treatment planning• Response to treatment – post CRT• Recurrence• Unknown primary
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%
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 7
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
FDG-PET in Head & neck cancer
Indications• Primary extent of tumour• Nodal staging. • Metastases• Treatment planning• Response to treatment – post CRT• Recurrence• Unknown primary
Management following CRT
Adjuvant ND after CRT is standard of care
Decrease risk of nodal recurrencePrognostic informationIncreased painFunctional disabilityCost
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 8
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
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 9
FDG-PET in Head & neck cancer
Indications• Primary extent of tumour• Nodal staging. • Metastases• Treatment planning• Response to treatment – post CRT• Recurrence• Unknown primary
Recurrent cancer of tongue
2009
2010
2009
Previous Ca Tongue. New palpable nodes ? recurrence
FDG-PET in Head & neck cancer
Indications• Primary extent of tumour• Nodal staging. • Metastases• Treatment planning• Response to treatment – post CRT• Recurrence• Unknown primary
Day 2 Session 1 Lecture 89:45am
Thursday 17th June 2010 10
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
Day 2 Session 2 Lecture 911:30am
Thursday 17th June 2010 1
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.
Day 2 Session 2 Lecture 911:30am
Thursday 17th June 2010 2
““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
Day 2 Session 2 Lecture 911:30am
Thursday 17th June 2010 3
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
Day 2 Session 2 Lecture 911:30am
Thursday 17th June 2010 4
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
Day 2 Session 2 Lecture 911:30am
Thursday 17th June 2010 5
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.
Day 2 Session 2 Lecture 911:30am
Thursday 17th June 2010 6
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
Thursday 17th June 2010 1
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’’
Adapting volumesAdapting 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
Day 2 Session 2 Lecture 1012:00 noon
Thursday 17th June 2010 2
Adapting volumesAdapting volumes
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
Partial blocking of fieldsPartial blocking of fields
Jaws positioned off cord to improve cord sparing
Partial blocking of fieldsPartial blocking of fields
Day 2 Session 2 Lecture 1012:00 noon
Thursday 17th June 2010 3
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
Day 2 Session 2 Lecture 1012:00 noon
Thursday 17th June 2010 4
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
Day 2 Session 2 Lecture 1012:00 noon
Thursday 17th June 2010 5
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
Day 2 Session 2 Lecture 1012:00 noon
Thursday 17th June 2010 6
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
Day 2 Session 2 Lecture 1112:30pm
Thursday 17th June 2010 1
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
Day 2 Session 2 Lecture 1112:30pm
Thursday 17th June 2010 2
Process
Reference image
Image acquisition
Image registration
Decision
Quality of Reference Image
2.5mm slice thickness
2.5mm DRR 1.25mm DRR
Quality of Reference Image
Small slice thickness for good resolution
Increased time on treatment unit on day 1
Mark reference at CT and isocentre on set
Quality of Reference Image
Process
Reference image
Image acquisition
Image registration
Decision
Before image acquisition
Day 2 Session 2 Lecture 1112:30pm
Thursday 17th June 2010 3
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
Day 2 Session 2 Lecture 1112:30pm
Thursday 17th June 2010 4
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
Day 2 Session 2 Lecture 1112:30pm
Thursday 17th June 2010 5
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
Day 2 Session 2 Lecture 1112:30pm
Thursday 17th June 2010 6
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
Check within tolerance
Check within tolerance
Check within tolerance
Off line protocols
Check within tolerance
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Correct for systematic error
NAL- No Action LevelOff line protocols
Check within tolerance
Check within tolerance
Check within tolerance
Check within tolerance
Check within tolerance
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
Day 2 Session 2 Lecture 1112:30pm
Thursday 17th June 2010 7
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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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 1
Imaging the ThyroidImaging the Thyroid
Dr Julie Olliff Dr Julie Olliff University Hospital BirminghamUniversity Hospital Birmingham
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 2
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 3
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 4
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 5
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 6
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 1
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 2
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 3
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 4
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 5
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 6
C-11 choline
Courtesy of Prof FazioMilan
78 yr oldpsa 4.6ng/mlrestaging
Courtesy of Prof FazioMilan
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 7
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 8
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
Day 2 Session 3 Practical Session2:00pm
Thursday 17th June 2010 9
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
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 1
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!
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 2
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
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 3
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
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 4
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
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 5
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
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 6
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”…….
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 7
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)
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 8
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
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 9
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
Data from a slide at ICCR by Gerry Battista
Performance/Cost (MIPS per $1,000)
PC-12TP-11
IMRT Plan
Rad-8
3D Plan
Data from a slide at ICCR by Gerry Battista
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 10
Calculations per second per $1,000
1 MFLOP
Data from a slide at ICCR by Gerry Battista
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
Data from a slide at ICCR by Gerry Battista
“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?
Day 2 Session 3 Lecture 124:00pm
Thursday 17th June 2010 11
“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
Day 3 Session 1 Lecture 139:30am
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
Day 3 Session 1 Lecture 139:30am
Friday 18th June 2010 2
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
Day 3 Session 1 Lecture 139:30am
Friday 18th June 2010 3
• 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
• Leaf Stability: Fence test
Dynamic MLC QA
• Leaf Stability: Fence test
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
Day 3 Session 1 Lecture 139:30am
Friday 18th June 2010 4
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?
Day 3 Session 1 Lecture 139:30am
Friday 18th June 2010 5
+ =
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
Patient specific QA : Dose Distributions
• 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
Patient specific QA : Dose Distributions
• Methods of dose distribution analysis– Profile comparison
– Isodose overlay• Distance to agreement (DTA)
– Dose difference• % difference
– Gamma index• DTA and % dose combined
Day 3 Session 1 Lecture 139:30am
Friday 18th June 2010 6
Patient specific QA : Dose Distributions
Profile comparison
Dose difference
TPS
Film
Patient specific QA : Dose Distributions
TPS
Film
Isodoseoverlay
Gamma map
Patient specific QA : Dose Distributions
• 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
Day 3 Session 1 Lecture 139:30am
Friday 18th June 2010 7
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
Day 3 Session 1 Lecture 139:30am
Friday 18th June 2010 8
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
Day 3 Session 1 Lecture 139:30am
Friday 18th June 2010 9
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
Day 3 Session 1 Lecture 1410:15am
Friday 18th June 2010 1
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 (%)
Complication-free cure = 35%
Complication-free cure = 35%
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 (%)
Complication-free cure = 35%
Complication-free cure = 65%
Day 3 Session 1 Lecture 1410:15am
Friday 18th June 2010 2
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)
Day 3 Session 1 Lecture 1410:15am
Friday 18th June 2010 3
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
Day 3 Session 1 Lecture 1410:15am
Friday 18th June 2010 4
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
Day 3 Session 1 Lecture 1410:15am
Friday 18th June 2010 5
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
Day 3 Session 1 Lecture 1410:15am
Friday 18th June 2010 6
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
Day 3 Session 1 Lecture 1410:15am
Friday 18th June 2010 7
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
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 1
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
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 2
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
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
Nutting et al Proc ASCO JCO 2009;27(2):799s
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
Nutting et al Proc ASCO JCO 2009;27(2):799s
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 3
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
Nutting et al Proc ASCO JCO 2009;27(2):799s
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]
Nutting et al Proc ASCO JCO 2009;27(2):799s
IMRT – Reducing the dose to the parotid gland in tonsil cancer
Conventional radiotherapy parallel
opposed fields
IMRT sparing left parotid
Nutting et al Proc ASCO JCO 2009;27(2):799s
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
Nutting et al Proc ASCO JCO 2009;27(2):799s
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
Nutting et al Proc ASCO JCO 2009;27(2):799s
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
Nutting et al Proc ASCO JCO 2009;27(2):799s
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 4
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
Nutting et al Proc ASCO JCO 2009;27(2):799s
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)
Nutting et al Proc ASCO JCO 2009;27(2):799s
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 5
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)
Nutting et al Proc ASCO JCO 2009;27(2):799s
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
Nutting et al Proc ASCO JCO 2009;27(2):799s
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
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
Updated Results of Phase I/II Dose Escalation Trial of Chemo-IMRT in
Advanced Laryngopharyngeal Cancer
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 6
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
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 7
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
Guerrero-Urbano 2008 R&O
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%
Guerrero-Urbano 2008 R&O
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
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 8
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
Day 3 Session 2 Lecture 1511:30am
Friday 18th June 2010 9
• 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
Day 3 Session 2 Lecture 1612:15am
Friday 18th June 2010 1
Common pitfalls in head and Common pitfalls in head and neck cancer imagingneck cancer imaging
Julie OlliffJulie OlliffUniversity HospitalUniversity Hospital
BirminghamBirminghamUKUK
ESH
COCHRANE SHANKS/JALIL TRAVELLING PROFESSORSHIP
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
Day 3 Session 2 Lecture 1612:15am
Friday 18th June 2010 2
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
Day 3 Session 2 Lecture 1612:15am
Friday 18th June 2010 3
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