Radiobiolgical aspects of Intensity Modulated Radiotherapy (IMRT)

1. Radiobiology of IMRT
Prof Amin E AAmin
Professor of Medical Physics
Radiation Oncology Department
Faculty of Medicine
Ain Shams University
&
Dean of Higher Institute of Optics Technology

2. IMRT vs 3DCRT
• We ask what are the basically new radiobiological issues of IMRT
compared to 3D-CRT?

3. IMRT And Conformal Therapy
• Technically, IMRT allows for dose shaping or sculpting,
both in terms of isodose contour shape, and the spatial
placement of non-uniform doses within the target.

4. IMRT And Conformal Therapy
• IMRT can therefore be seen as minimizing the
volume of the target which receives a lower than
desired (prescribed) dose, due to required
avoidance of normal tissues.
• As implied, however, taking advantage of IMRT
relies critically on our knowledge of tumor and
normal tissue dose-volume factors.

5. Radiobiological Issues in IMRT
1. The increased involvement of quantitative clinical
radiobiology with the prescription and treatment
planning process (e.g., in the specification of dose-
volume constraints).
2. The increased need for reliable information on dose-
volume effects, to safely guide prescriptions.
3. Increased need for information about the usefulness of
non-uniform target dose distributions (i.e., dose
distributions with small cold volumes and/or large boost
volumes).

6. Issues’Answers
• Because IMRT dose distributions vary greatly between
individuals, it is impossible to run clinical trials which
answer all the relevant questions about dose-volume factors
needed for treatment planning.
• Any particular clinical trial is designed to, at best, answer
one particular quantitative question.
• No clinical trial can be designed to determine the correct
dose-volume NTCP model and additionally yield an
accurate determination of the model parameters.

7. Dose-Rate Effects in IMRT
• External beam radiotherapy is usually delivered with
dose rates of 1-4 Gy/min delivered to several different
fields within a 10 min. period.
• Steel (2002) pointed out that experimental data, from
both in vitro and clinical experience with brachytherapy
treatment, show that fewer cells are killed per unit dose
as the dose-rate is reduced.

8. Dose Rate Effect
The dose-rate effect in normal
tissues of the mouse, as compiled by
Steel (1987). ‘E’, epilation; ‘L’,
lung; ‘G’, GI; ‘M’, bone marrow.
There is a significant increase in
effect (and fall in the dose required
to reach an endpoint) between 10
cGy/min (2 Gy in 20 minutes) and
100 cGy/min (2 Gy in 2 mins.)
This may have implications for slow deliveries of IMRT.

9. Dose-Rate Effects in IMRT
• In 2000, Fowler showed that measured residual
damage due to radiation in the form of single-strand
breaks or double-strand breaks of DNA are time
dependently repaired.
• That is, the number of residual lesions is reduced in
proportion to the inverse of the elapsed time: the
same fractional reduction is seen in going from 10
minutes to 20 minutes as in going from 30 minutes to
60 minutes (a factor of two in both cases).

10. Reduction Of Radiation Effectiveness
With Time Protraction
• The biological effectiveness of radiation depends on
the dose rate.
• Radiation effectiveness may be reduced in a range of
5-10% level when dose delivery is protracted from 5
up to 20 minutes, as seen in calculations and
measured cell kill experiments.

11. Effect of Time Protraction in
IMRT
• One potentially important implication for IMRT is that 2 Gy
fractions delivered effectively in 1-2 minutes may be slightly
more biologically effective than doses delivered in segments
over, say, 20 minutes.
• This effect, predicted to be about 5-10% from repair kinetics
models, has also been observed in vitro.

12. Effect of Time Protraction in
IMRT
• Animal dose-rate studies also show a significant difference
between 1 Gy/min and 1 Gy/10 min dose rates. This implies
that ‘fast’ IMRT may be biologically more effective than
‘slow’ IMRT.

13. Impact of Prolonged Fraction
Delivery Time on Local tumor control
• Wang et al (2003) studied the potential impact that fraction
delivery time has on local tumor control using the LQ model
and the radiosensitivity parameters derived from clinical data
for prostate cancer.
• They predict that the time to deliver a fraction using static
IMRT may decrease the EUD and TCP.

14. Sensitivity to Fraction Delivery
Time
• Some investigators pointed out that tumors with a low a/b
ratio and a short half-time for sublethal damage repair,
such as prostate cancer, will likely be more sensitive to
fraction delivery time than tumors with larger a/b ratios
and/or longer repair half-times.
• On the other hand, some other investigators showed that
tumors with unusually are less sensitive to fraction
delivery time.

15. Sensitivity to Fraction Delivery Time
• Therefore, the relationship with the α/β ratio remains unclear
and requires further investigation.

16. Compensation Of Reduction
In Effectiveness
• Results of some studies suggest that if IMRT with a
delivery time longer than 10–15 min is employed, the
prescription dose may have to be increased to
compensate for the reduction in cell killing due to the
increased sublethal damage repair.
• The prescription dose can be escalated by increasing
fractional dose and/or by increasing the number of
fractions.

17. Shortening Fraction
Delivery Time

18. Static vs. Dynamic IMRT
• To shorten the fraction delivery time, dynamic IMRT can
be used, instead of static (step-and-shoot).
• Dynamic IMRT has been shown to result in 2–2.5 times
less total delivery time compared with static IMRT.

19. VMAT
• An example of dynamic IMRT is volumetric intensity-
modulated arc therapy (RapidArc or VMAT) which cab
be delivered in equal or less time as compared with
conventional treatments.

20. Tomotherapy
❖Another example of dynamic therapy
which reduce the fraction delivery time
is Tomotherapy
❖In Tomotherapy every cell receives its
full complement of dose in less than 2
minutes. In IMRT using conventional
accelerators the time from first to last
photon may be 20 min or more
allowing significant tumour cell
recovery.

21. Flattening Filter
• Conventional medical linear
accelerators delivering photon
beams are equipped with a
flattening filter (FF) in order to
allow delivery of homogeneous
dose distributions with broad
beams.

22. FFF
• The main advantage of FFF is increasing the dose rate and
reducing treatment time.
• In FFF beams the dose rate increase in two to four times
higher than standard beams.

23. Shortening Of Fraction Delivery Time
By Reducing The Number Of Segments
• Another way to reduce IMRT delivery time is to optimize the
leaf sequencing and reduce the number of segments.

24. Direct Aperture Optimization (DAO)
• An example of inverse planning algorithms that
use fewer segments while not sacrificing too much
on dose uniformity and conformity are being
developed is the direct aperture optimization
(DAO) method.
• The IMRT plans generated by DAO can be
delivered within 10 min using step-and-shoot
technology.

25. Superiority Of IMRT Over 3DCRT
• Currently, phase Ⅲ randomized trials demonstrated
superiority of IMRT over conventional techniques in terms of
both acute and late complications after breast conserving
surgeries (Ozyigit and Gultekin (2014).
• Dosimetric trials showed that IMRT also improves breast and
regional lymphatic coverage while decreasing radiation doses
to heart, lungs, and contralateral breast tissues compared to
old-fashioned radiotherapy techniques