TCP & NTCP for Treatment Planning

& Radiobiology of Particle Beam

Therapy
Presented By: Alka Kataria
Moderator: Mr. Ranjit Singh
 RADIOBIOLOGY:
• Study of the effects of the ionizing radiation on the
biological systems.
• The action is very complex, involving physics, chemistry
and biology
- Different type of ionizing radiation
-Energy absorption at the atomic and
molecular level leads to biological damage
-Repair of damage in tissue
 Fractionation
• A method in which total
dose of radiation is divided
into several, smaller doses
over a period of several
days.
• This maximizes effect of
radiation on cancer and
minimizes the negative
side effects.
Hypofractionation is a treatment regimen that delivers
higher doses of radiation in fewer visits.
• Logic behind treatment- applying greater amounts of
radiation works to lower the effect of accelerated
tumor growth that typically occurs during the later
stages of radiotherapy .
Hyperfractionation: divides same total dose into more
deliveries.
• Treatment are given more than once a day.
• To reduce the late effect but same or better tumor
control.
 6R’s of radiobiology:
•REPAIR
•REOXYGENATION
•REPOPULATION
•REDISTRIBUTION
•RADIOSENSITIVITY
•REMOTE BYSTANDER EFFECT
Note: Repair and Repopulation tends to make the
tissue more resistant to a second dose of radiation;
while reassortment and reoxygenation tends to
make it more sensitive.
 REPAIR:
• Primary reason for fractionate radiotherapy.
Three types of damage that Ionising Radiation can cause to
cells:
 Lethal Damage : Damage which is fatal to the cell.
 Sub lethal Damage : Damage which can be repaired before
the next fraction of radiation is delivered.
 Potentially Lethal Damage : It can be repaired under certain
circumstances (usually when the cell is paused in the cell cycle
due to external factors).
• Now by splitting the radiation dose into smaller parts
(fractionation) cells are allowed time to repair sub lethal.
• Tumour cells don’t always recognize they are being damaged
and don’t repair themselves.
THIS LIMITS THE DAMAGE TO NORMAL CELLS.
 REOXYGENATION:

• Tumors contains mixture of hypoxic and aerated

cells.
• A dose of x rays kills a greater proportion of oxic than
hypoxic cells.
• If fractionation is such that reoxygenation of hypoxic
cell occurs ,
• Thus then these relatively oxic cell can be killed
easily.
 REPOPULATION:
• In between fractions normal as well as tumour cells
repopulate .
• Fractionation helps in certain cases where the normal
tissues’ response time is shorter than the time to have all
treatments.
• Suppose normal tissue started repopulating in 4 weeks,
and the total treatment time is 6 weeks.
• This means that in the last two weeks the normal tissue has
started to repopulate.
• But, If the tumour cells start to repopulate before all the
treatments have been delivered there is an accelerated
growth of the remaining tumour towards the end of the
treatment.
• We have to plan fractionation accordingly .
 Redistribution:
• During radiotherapy cells may be at different parts of
cell cycle.
• Cells in S-phase are radio resistant, whereas those in
late G2 and M phase are relatively sensitive.
• Thus dose of radiation will kill a lot of the sensitive
cells and less of the resistant cells.
• If a second dose of radiation is delivered some time
later, some of these cells will have left the resistant
phase and be in a more sensitive phase, allowing
them to be killed more easily.
 RADIOSENSITIVITY:
LAW OF BERGONI AND TRIBONDEAU
• Cells which are actively dividing and are
undifferentiated with a long mitotic future are more
sensitive than cells which have stopped division and
are differentiated.
• It accounts for the intrinsic radio sensitivity or radio
resistance in different cell types.
• Radiosensitive cells include hematological cells,
epithelial stem cells, gametes and tumor cells from
hematological or sex organ origin.
• Radio resistant cells include myocytes, neurons and
tumor cells such as melanoma or sarcoma.
 REMOTE BYSTANDER EFFECT:
• Occurs when non irradiated cells located nearby
irradiated cells undergoes cellular damage similar to
that of radiated cells.
• Acc. To bystander theory, non targeted cells can also
present signs of radiation damage that ultimately
leads to cell death.
• Primarily occurs when neighbouring cells are in gap
junction communication with irradiated cells.
• This effect occurs in both tumor and normal cells.
 SERIAL AND PARALLEL ORGAN:
• FSU: A functional sub-unit is a compartment of an
organ that performs part of the organs function.
FSUs may be arranged in serial, parallel, or a
combination of both.
• Serial organ: FSU are arranged involves in a line
with the others.
 If a single FSU fails, then the organ experiences
significant deleterious effects.
 Dmax is considered while planning.
 Ex. spinal cord , gastrointestinal tract, optic nerve
etc.
• Parallel organ: FSU are arranged such that each FSU
is able to function independently .
 Loss of a single FSU leads to a slight decrease in
function of the organ.
 No functional damage will occur until a critical no. of
FSU are irradiated.
 Ex. – liver, kidneys. Organs with parallel arrangement
of FSUs are more sensitive to volume effects.
• Some organs present a combination of serial and
parallel FSU arrangement.
 Ex. The lung airways are arranged in serial, but the
smaller airways have a parallel FSU setup.
 Tumor control and normal tissue
complication:
• Aim of RT- sufficient
dose to tumor to
achieve local control
without introducing
severe complication to
normal tissues.
• These conflicting aims
can be quantitatively
described by dose
response curves for
tumor and normal
tissue.
 Aims of biological models in TP:
1. Transfer of one treatment regime to biologically iso-
effective new regime without predicting absolute
values of TCP and NTCP.
2. Calculation of TCP & NTCP value to compare either
competing treatments plans for an individual
patients or different treatment techniques.
3. Integration of TCP/NTCP model into function of
dose optimization algorithm to generate biologically
optimized treatment plans.
 TCP model based on Poisson distribution:
• Model was derived using linear quadratic model which
describes killing of cell by radiation except at dose below
0.6Gy.
S.F=exp(-αd-βd2)
• For a fractionated EBRT slope of curve nearly given by α only
(α/β=high).
For n fraction each of dose d thus total dose D, the avg. no. of
surviving cell-
Ns ≈No exp[- α D(1+β d/α)]
• Next step is to include end point i.e eradication of the tumor.
It is assumed that a tumor is only controlled when every
single colonogenic cell is eliminated (target cell hypothesis of
tumor control)
• The probability that no single colonogenic cell
survives is given by Poisson statistic

• the desired probability corresponds to y=0,

• As, N=Ns=NOS ,then

(for n=1)

(for D=nxd)
 CONT….
• Proliferation can be included
in TCP expression by adding
ϒ(T-TK), where ϒ=ln 2/Td,
• Td is the average doubling
time, T is the overall
treatment time, and TK is the
time at which proliferation
begins.
 TCP in terms of ϒ50 and D50 :
• As, TCP = exp(−N p (D))
If it is assumed that cell survival can be described by single-hit
mechanics,

• Above eq. can be rewritten in terms of the two parameters

describing the dose and normalized slope at the point of 50%
probability of control, D50 and γ50 :

• Using the assumption of independent sub volumes, for the case

of heterogeneous irradiation, the overall probability of tumor
control is the product of the probabilities of killing all clonogens
in each tumor sub volume described by the DDVH:
 TCP model incorporating
radiobiological data:
• This includes a second TCP model that is parameterized
in terms of fundamental cellular radiation response
characteristics.
• This TCP incorporates the effect of tumor repopulation.
• expression predicts that the TCP after the delivery of n
fractions is

where λ is the rate of cellular repopulation, Tk is the time

between the kth fraction and the first fraction, and Ps(Tk)
is the cell survival after the kth fraction
• If complete repair of sub lethal cellular damage
between fractions takes place then, the LQ
prediction of cell survival after the kth fraction will be

• where α and β are cellular radio sensitivity

parameters, D is the total dose delivered in the n
fraction of treatment and it is assumed that the dose
delivered in each fraction is the same.
 Poisson TCP databases:
There are two databases:
• a “default” one, which cannot be altered by the user.
• a “user” database, for which the user is allowed to add
and delete database entries via a menu-driven
interface.
Each database entry includes the following data:
• model name, organ/endpoint or tumor/grade
descriptor, parameter values and the clinical data on
which it is based.
A large collection of tumor dose-response parameters
(D50and γ50) extracted from multi-institution tumor
data for many different tumor sites and grades has
been included in “default” Poisson database.
 NTCP:
• NTCP is a important index for ranking treatment plans.
• It reduces the large amount of data of 3-D dose
distribution to a limited number of numerical indices.
• Thus makes the comparison of a number of rival plans
more efficient.
• In addition, NTCP nominally represents an endpoint,
which often determines the acceptability of a
treatment plan, that is, whether the tolerance of
normal tissues has been respected or exceeded.
• The NTCP models predicts the probability of a
complication, changes with volume irradiated at a fixed
dose i.e. volume effect.
• The extent of the volume effect is dependent on the
architecture of the respective tissue(serial & parallel
organ),
 L-K-B Model:
• A four-parameter model.
• This describes complication probabilities, using
(clinical) tolerance doses for different irradiated
volumes as input data.
• The tolerance doses for different volumes are
related through a power law, and thus the clinical
data are used to determine the magnitude of the
volume effect.
• In spite of this flexibility, the L–K–B model does not
exhibit a threshold effect with volume.
• In this model, the complication probability P(D,V) for
a uniform irradiation of a normal tissue volume V
with a dose D is given by

• The four parameters of the model are given by

TD50, m, n and Vref which have to be adjusted to
clinical data for each tissue type.
• TD50(1), the dose to the whole organ which would
lead to complication in 50% of the population (note
that TD50(V/Vref) is to be read as the TD50 at partial
volume V/Vref).
• Vref, a reference volume, which in many cases will be
the (whole) organ volume.
• m, a parameter representing the steepness of the
dose–response curve.
• n, the exponent of volume in the power law that
relates the tolerance doses for uniform whole and
uniform partial organ irradiation.
• represents the volume effect: when n is near
unity, the volume effect is large and when it is
near zero, the volume effect is small.
• a large volume effect implies that the NTCP
correlates with the mean dose, while a small
volume effect implies that it correlates with
the maximum dose in the organ.
 The Critical Element Model:
• Assumes that an organ consists of a number of
identical FSU, each of them responding
independently to radiation.
• The term “critical element” means that a
complication occurs, if a single FSU is inactivated
(spinal cord, brain or bowel).
• If P(D,v) is the complication probability that a dose D
to the fractional volume ‘v’ will produce a
complication, [1- P(D,v)] is the probability that no
complication occurs.
• If a whole organ consisting of N equal-sized
compartments (each of volume v=1/N) is uniformly
irradiated with a dose D, the probability that the
organ escapes injury P(D,1) is given by
• the product of the probabilities that each sub-
volume escapes injury. P(D,v) can then be expressed
by
P(D,ν ) =1− [1− P(D,1)]v
• for non uniform dose distributions {D}
P(D,ν ) = 1-Π[1− P(D ,1)] Δvi.
 The Critical Volume Model:
• In contrast to element model, an inactivation of a single FSU
will not lead to complication in the organ as the organ
function will be maintained by the remaining FSUs.
• If more than a critical number of FSUs will be inactivated a
complication will occur( lung, kidney, liver, or parotid
glands).
• If an organ is consist of N parallel organized and
independently responding FSUs, then
• probability that more than M FSUs are inactivated by an
uniform dose D is given by

• where PFSU is the dose-dependent probability for

inactivating a single FSU.
A TCP-NTCP estimation module using DVHs and known
radiobiological models and parameter sets
• Radiotherapy treatment plan evaluation relies on an implicit
estimation of TCP and NTCP. arising from a given dose
distribution.
• Radiobiological modeling helps in ranking the treatment plans
via a more explicit determination of TCP and NTCP values.
• Due to limited predictive capabilities of current radiobiological
models prevent their use as a primary evaluative tool.
• A computational module has been developed for estimating
the TCP and the NTCP arising from a dose distribution
calculated by a treatment planning system and characterized
by DDVHs.
• The models included in module are- sigmoidal dose
response, Critical Vol. NTCP, a Poisson TCP, and a TCP
model incorporating radiobiological parameters.
• A number of sets of parameter values for the different
models have been gathered in databases.
• Applications of the system include the following:
 -comparing radiobiological predictions of outcome for
different treatment plans or types of treatment.
 - comparing number of observed outcomes for a cohort
of patient DVHs to the predicted number of outcomes
based on different models/parameter sets.
 - testing of the sensitivity of model predictions to
uncertainties in the parameter values
 Particle beams in RT:
• The desired biological effect are the resultant of
ionizations produced by radiation.
• Classes of particle radiation used in RT:
 Light particles- proton, neutrons , alpha particles.
 Heavy particles- fully stripped carbon, neon, silicon
and argon ions.
• Particle beams has greater effect per unit dose than
conventional radiation.
• Also, have very different depth dose absorption
profile compared with neutron and conventional
radiations.
 Microdosimetry:
• Gamma ray deposits much
of their energy as single
isolated ionization or
excitation resulting in a DNA
damage which can be
repaired efficiently by
enzymes within nucleus.
• Alpha particles produce
fewer tracks but intense
ionization in each track
leads to more severe
damage which would be
difficult or even impossible
to repair.
Thus alpha radiation produces steeper survival
curves and allow less cellular recovery than x- rays.
 Biological effects depends on LET:
• As LET increases - radiation produces more cell killing
per gray.
• High LET damages are less likely to be repaired
correctly.
• For same type of particle beam, LET generally
increases with decreasing particle energy.
• However, 2.5 MeV α-particle are less efficient than
4.0 M eV α-particles even though they have a higher
LET; this is due to phenomenon of overkill.DGM PLOT
LET α (charge/velocity)2
 RBE depends on dose:
• RBE is not constant but depends on the level of
biological damage and hence on dose level.
• Low LET and very high LET radiations are inefficient
because deposits much energy than required.
• Optimum LET is around 100 KeV µm-1 but it does
vary with different cell type and spectrum of LET
values in radiation beam as well as the mean
LET.DGM 16.3 & NEXT
 Response of the different tissue with
high LET radiation:
• For the same biological effect, less change in total dose with
fractionation for high LET than compared to low LET.
 Comparison of RBE for skin and kidney exposed to
two different neutron beams:
• RBE for d(16)-Be neutrons in kidney was greater than in skin
at an X-ray dose per fraction of 2Gy , but that is much lower
for highly penetrating p(62)-Be neutrons.

p(16)-Be p(62)-Be
Biological advantages of high LET in RT:
1. Differential radio sensitivity b/w poorly oxygenated
and well oxygenated cells can be reduced by using
high LET( therefore tumor sites where hypoxia is a problem high LET might
benefit in same way as hypoxic cell sensitizers)
2. Differential radio sensitivity due to cell cycle position
can be considerably reduce with high LET
radiation.(beneficial in some slowly growing tumor or x ray resistant tumor)
3. Range of radiation response of different cell type is
reduced with high LET radiation than x-rays.(this reduced
range affects the benefit expected i.e. balance b/w normal tissue and tumor
response explanation from book.)
Physical basis of charged particle beam
therapy:
• With x-ray beam therapy, absorbed increases very
rapidly within short distance in which electronic
equilibrium occurs and then decreases exponentially
with increasing penetration.
• Neutrons are also uncharged and their depth dose
characteristics are similar.
• In contrast, ion beams increases their rate of energy
deposition as they slow down with increasing
penetration, finally stopping and releasing intense
burst of ionization called the Bragg’s peak.
•Broad peak is obtained by
superimposing other beams
of different and ranges
achieved by passing primary
beam through a rotating
wheel with sectors of
different thickness and
angular width of plastic
sheet.
•This entire spread out peak
can be adjusted to cover the
tumor volume.
•Thus ratio of tumor to
normal tissue dose
compared with conventional
photon therapy.
• Example

• This highly localized dose max. presents the

usefulness of such beams in delivering therapeutic
doses to tumors located at some depth in body while
minimizing the dose in overlying normal tissues.
Some possible treatment plans with heavy ion beam
 Bragg peak for C-12:
Fragmentation tail: no sharp dose
fall off .
• Slight decrease in slope is
caused by energy loss straggling
and nuclear interaction with
atoms of the medium.
• These fragments are
intermediate to low energy ions
of boron, beryllium or lithium
etc.
• These fragment travel non –
negligible distance beyond range
of C-12 and deposit their energy.
C-12 have higher LET than proton thus more therapeutic
advantage , therefore can be used in suitable tumors.
 Summary for charged particles:
• Protons have superb depth dose distribution and have
radiobiological properties similar to x-rays. Thus proton
and helium ion will play key role in better RT in coming
years for the lowest cost.
• Neutrons have no dose distribution advantage over MV
x-rays but may be useful because the high LET.
• Heavy ions have better dose distribution than x-rays
than x-rays , also higher LET depending on type o LET of
particle.
 Cont…
• Argon ions have high LET but in practice they break
up so readily that only limited penetration is useful.
• If heavy ion therapy has future, most probably
carbon, neon, silicon ions will be the particles.
High LET rad. may be clinically useful in selected cases
 References:
• Basic Clinical Radiobiology ; G. Gordon Steel
• Handbook of Radiotherapy Physics
• Journal of Applied Clinical Medical Physics
• AAPM Report - 166