Biology: The views of a concerned end user

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Biology The views of a concerned end user
A. W. Beavis PhD SRCS

• Principal Physicist
• Department of Radiation Physics,
• Princess Royal Hospital
• Hull and East Yorkshire Hospitals (NHS) Trust and
  University of Hull

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I am not a RadioBiologist!
More questions than answers!!
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Princess Royal Hospital, Hull

• Mr. Viv. Whitton
• Head of Rad. Physics
• Principal Physicist
• Senior Physicist
• 3 x Junior (B8-B13)
• 2.5 Dosimetrists
• Have new posts (Physicists, dosimetrist)
  available in next three years in run up to
  opening new department TWICE current size
• Radiographer vacancies

• 3 Varian Linacs (600C, 600CD, 2100C)
• (6, 10 MV 6-20 MeV)
• Odelft Simulator
• Dedicated Picker PQ5000 CT scanner
• GE Signa 1.5T MRI
• Philips Intera 1.5T MRI
• GE Signa 3.0T MRI
• 3 CMS FOCUS w/s networked (PC) Focal products
• SIITP, Focal fusion
• 100 patients (total) per day

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Looking to the future how do we utilise the
Power of IMRT?

• Having implemented the weaponry
• We need to develop the rules of engagement
• When to use IMRT
• How to use IMRT
• We need to develop the intelligence to find the
  tissue to target!
• Dose escalate to PTV
• Dose escalate to boost regions
• Conformally avoid organs at risk

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PRH Pancreatic Phase I dose escalation trial

• Began our clinical IMRT service Feb 2002
• 4th clinic in UK (Marsden, Christie, Ipswich,
  Hull) to implement IMRT
• First European FOCUS users to use CMS FOCUSIMRT
• We decided to make first patients part of a trial
  
• As much as anything to test our ability to
  perform clinical service and our capability of
  doing it safely (escalation via concomitant
  boost)

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IMRT/ Inverse planning in CMS FOCUS

• SIITP algorithm
• Xing et al. Med Phys 25 1845-1849 1998
• Fast iterative algorithms for 3D inverse
  treatment planning.
• Implemented as a fully integrated part of the XiO
  (FOCUS) system
• Focal VUE - a PC based tool - enables review and
  comparison of different plans on remote PC
  stations
• Implemented using Step and shoot
• We are collaborating on adding more leaf
  sequencing options, including dynamic and novel
  approaches

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Radiobiology issues tumour targeting

• Cold/ Hot spots
• Multiple target doses/ diff dose rates per
  fraction
• NTCP can we use the data in the literature?
• TCP can we use the data in the literature?
• Image Guided Therapy how does this change the
  game?
• Biological Target Volume definition

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Radiobiology issue 1 cold/hot spots

• The optimisation routines and the sequencing
  routines we use are generally separate entities
• The optimisation routines are not actually good
  enough
• Cannot deliver precisely the fluence patterns we
  wish!
• Result
• Cold spots
• Hot spots not important? (well lets see)

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Prescription for an IMRT plan?
cover the PTV with 95 isodose does NOT mean
allow 5 area of the PTV to receive any dose less
than Dpres - Two VERY DIFFERENT
distributions!
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Example IMRT concomitant boost plan
PTVboost
PTVconven
Good plan?
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DVH IMRT zero boost patient

• PTV
• Spinal Cord
• Stomach
• R. Kidney

100 of PTV receive 95 of prescription
dose, Monitor vol. Rec. gt107
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Why is this important?

• GTV? CTV required to account for microscopic
  tumour spread
• Cell division (Mitosis) more ACTIVE at the outer
  edges of tumours (vascularity)
• Cannot assume reduced DENSITY of cells anywhere
• CTV? PTV required to ensure we irradiate the CTV
  adequately (motion, set up error etc)
• So compromising the PTV coverage may result in a
  non-tumourcidal dose being applied to the CTV!

95 isodose
GTV Gross target volume CTV Clinical target
volume PTV Planning target volume
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PTV is an envelope within which the CTV is
present with 100 certainty

• Cannot assume any edge of the PTV is less at risk
  from being under-irradiated
• (May reduce the risk.)

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Tome and Fowler. On Cold spots in tumor
subvolumes Med Phys 29(7) 1590 2002
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Hot spots?

• Dont matter so long as they are inside the PTV?
• A hot spot close to a critical organ at risk may
  present a problem!
• may migrate into this critical organ
• Maximum effect may be diluted due to motion etc.
  BUT the 110 spot on the plan may translate to an
  average/ mean dose of gt90 of prescribed dose
  (greater than tissue tolerance)
• Normal tissue hotspots
• Therapeutic margin should not be narrow!

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Radiobiology issue 2 Dual doses

• Concomitant boosts (SIB)
• Assume can make the distribution homogeneous
• Deliver a standard conformal dose to the standard
  conformal PTV
• Apply a boost dose to an identified sub-volume
• PTV2 created from some means
• Any Biological effects to consider because we
  give higher dose per day than normal?

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Fraction doses?

• In North of England (!)
• Tend to use larger doses/ fraction in variety of
  treatments (40 Gy in 15 Breast, 55 Gy in 20
  prostate)
• Therefore, we have 50 years experience of giving
  large doses per fraction in a limited range of
  sites
• So greater than 2 Gy/ within tumour not expected
  to cause a problem?
• Can we go higher?
• i.e. 3 Gy/ (to give a prostate boost of 60Gy in
  20)

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Normal tissues getting higher doses?

• The CTV ? PTV margin contains some normal tissues
• Generally considered safer to irradiate these in
  order not to compromise tumour control (via
  fractional geographical misses)
• Dose escalation (either by Concom. Boost or to
  whole PTV) raises the maximum dose to the normal
  tissue
• A problem?
• Critical Organ hot spots since IMRT reduces the
  volume of OAR irradiated to higher doses may keep
  the EUD value constant?
• Normal tissue may be too close to the tumour and
  so receives the escalated dose every fraction.

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Radiobiology issue 3NTCP

• Data/parameters used for NTCP models.
• Mainly, collected retrospectively, Emami data
• Most of us will rely on the literature for input
  data TD50, n, m

Burman, C., Kutcher, G. J., Emami, B., and
Goitein, M. Fitting of normal tissue tolerance
data to an analytic function. Int. J. Radiat.
Oncol. Biol. Phys. 21, pp. 123-135 (1991).
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Historically derived NTCP data

• In the fitting of the historical data they must
  have assumed (perfect) plan and (perfect)
  delivery
• The clinically observed outcomes MUST have motion
  convolved in by default
• May be that (probably!?!) effect is averaged out
• BUT, Contemporary 3dCRT/ IMRT aims to reduce
  motion so OARs will be given different doses to
  those assumed in fitting that produced TD50 , m,
  n for the stated outcomes
• So, New data needed to use NTCP models.
• Same is true for EUD, ..

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The NTCP Workspace
Enter the organ/structure for which to model NTCP
Enter uniform dose which results in 50
complication
Enter the n parameter describing the volume
dependency of the organ
Enter the m parameter modeling the slope of the
NTCP curve
Enter the clinical end point
Enter the reference volume corresponding to the
TD50
For documentation purposes only not needed for
NTCP calculation.
Mouse can be used interactively in the TCP window
to automatically increase or reduce the total
dose delivered by all external beams.
Typical RTPS interface that encourages user to
put the numbers in!
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XiO/ FOCUS Online reference to published NTCP
parameters
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Radiobiology issue 4 TCP

• Tumourcidal doses used in general
• Again, motion convolved into majority of the
  literature data by default
• Only recently that hetrogeneity corrections have
  been universally accepted and used!
• Only recently that accurate calculations have
  been adopted and used
• so tumour doses have always been diluted (best
  estimate) to some degree!

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Assuming we achieve better localisation

• Do we have to give as much as we think to obtain
  an iso-effect?
• i.e. prostate if rectum changes shape it
  allows PTV to move ant/post
• 68 of cancers arise in the PZ so if the tumour
  is in the posterior lobe then these cells may be
  spared on some fractions.
• Is 3dCRT dose escalating by default because more
  attention is given to localisation etc..?

Courtesy Di Yan, William Beaumont and Marcel Van
Herk, NKI Amsterdam
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Radiobiology issue 5 IGT

• Image guided therapy/ next breed of IMRT
• Track tumour each day
• Gated therapy, cone beam kV-CT, Helical
  TomoTherapy
• Now, assuming we know more about where tumour is,
  do we need to dose escalate?
• Do we need to adhere to the traditional
  critical Organ tolerance.

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I.G.T
MV CT from a Tomotherapy device

• Can we abandon the CTV? PTV margin growth?
• target the CTV in real time? AND plan the delivery

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Radiobiology issue 6 BTV

• Defining the targets/ OARs themselves
• Biological (planning) Target Volumes
• Target the active part of the tumour architecture
• Rather than trying to escalate the dose to the
  whole PTV boost a small volume
• Utilise conformal effect further
• Avoid cliping OARs with escalated dose
• Avoid having to shrink PTV margins round tumour
  to ensure miss OARs and risk geographical
  misses of tumour edges

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?

• IMRT offers the capability to BOOST the dose to
  the actual tumour potentially increasing the
  tumour control probability

PTV1 Prostate
PTV2 Boost the conventional dose??
55 Gy covering PTV1
65 Gy covering CTV2 PTV2 is covered by 60 Gy
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MR Spectroscopy data for Peripheral Zone (PZ)
Carcinoma and normal PZ data
T2 image showing MRS sampled voxels

• Single voxel measurements showing normal PZ
  Citrate sample and that for diseased (Ca.) tissue

Data from G.P. Liney et al. NMR in Biomedicine 12
39-44 (1999) For excellent review see Pickett
et al. IJROBP 44(4) 921-929 (1999)
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Dynamic contrast-enhanced-MRI (DCE)
Another method (relevant to more tumours)

• takes advantage of the angiogenesis inherent with
  cancers
• the vascularisation is denser and has poor
  integrity
• intravenous administration of Gadolinium
• T1-weighted imaging
• a series of images are collected following the
  injection

G.P. Liney et al. NMR in Biomedicine 12 39-44.
(1999)
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T1 weighted images at different time intervals
post contrast injection.
Tumour (volume) in Peripheral Zone
138
210
t 0
453
Benign disease in Central Gland BPH
Enhancement factor, EF(t)
Normal tissue i.e. RHS of PZ shows no/little
uptake
Note The rectal probe is not used for
Radiotherapy planning patients!
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Transfer of information into the Radiotherapy
Treatment planning process
The simplest is to threshold the data set to
identify all pixels that enhanced above a
certain (pre-determined) value then label them in
a binary fashion
These modified pixels can be overlaid onto a
(registered) T2-weighted image then send to
treatment planning system.
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Role of DCE in verification of (conventional)
radiotherapy efficacy?
A
B
Plot of PSA level .v. time. A represents the time
of the pre-Radiotherapy MRI-DCE scan and B the
post-treatment scan.
Enhancement factor plots .v. time for a patient
before conventional radiotherapy.
Plots after treatment
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Conclusion Biological optimisation?

• This is most probably the way forward
• Optimise the fluence distributions using
  biologically derived cost functions
• Care is needed?
• Need to define our dose .v. measured outcome with
  care so apples apples
• 3dCRT 3dCRT, IMRT IMRT

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Conclusion

• Obviously, networking of existing groups round
  the world will help us gain experience more
  quickly
• Congratulate Robert on organising meetings such
  as this help us sing from the same hymn sheet?

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Thanks to

• Mr. V. J. Whitton
• Mr. S. Howey
• Dr. Gary Liney (MRI)
• Planning staff at PRH!
• CMS for their support, interest and financial
  help regarding this meeting.

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And to Mr. John Saunderson