Aubrie Rice

Rad Sci 4670

Literature Review

LET painting with Hypoxic Tumors

Aubrie Rice
December 09, 2015

Introduction
1

Aubrie Rice
Rad Sci 4670
Literature Review
Tumor hypoxia is a major concern in radiation therapy when it comes to tumor control.
Research has been done to try to find ways to increase tumor cell-kill with these tumors that are
so radioresistant with our most commonly used photon and even proton beams. Such research
has found that high-LET beams more efficient at tumor cell-kill due to hypoxic cells being less
prone to hypoxia induced radiosensitivity with these high-LET beams.1,3 Due to this finding,
high-LET radiotherapy that utilized fast neutrons was used for a certain time for therapy.3
However, it was later found in studies such as the one conducted by Koh et al, that severe side
effects resulted from this type of treatment which concluded the use of fast neutrons.2,3 Following
these studies, a fairly new method of treatment has been introduced that is called LET-painting. It
attempts to restrict high-LET radiation to compartments that are found to be hypoxic, while
applying lower LET radiation to normoxic tissues.4 This strategy of treating looks promising
since it could increase hypoxic tumor cell-kill while decreasing normal tissue side effects that
were noted in studies such as Koh et al.2 The studies by Bassler and Jkel et al, Bassler and
Toftegaard et al and Chang et al test this new technique known as LET painting.3,4,5
Body
In their article, Bassler and Jkel et al research the possibility of better tumor control with
the low OER of high-LET beams and how this can be used.3 The study uses both carbon ion and
proton treatment planning. By using a software called pytrip, Bassler and Jkel et al compared
dose distribution to LET distribution.3 They found that very similar dose distributions could have
very different LET distributions.3 Two configurations were compared, the first was four flat
carbon ion fields at 0, 90, 180, and 270 degrees, each targeting a box shaped PTV (5 cm3).3 The
second configuration was four flat carbon ion beams again, but this time the depth of the spread
out Bragg peak (SOBP) was reduced so that each field only covered the proximal half of the
PTV.3 It was found that the two configurations showed very similar dose distributions but when
comparing LET, the second configuration resulted in higher LET in the middle of the target
volume.3 This result was due to the high LET being concentrated at the distal portion of the
SOBP. Another finding of this study was that carbon ions can be used to increase dose in certain
tumor compartments.3 Three fields were used in this configuration: a proton field delivering 50%
of the dose to a sphere that was 10 cm in diameter, and two additional spherical fields that were 1
cm in diameter were placed within the larger sphere and boosted to 100% of the dose with

Aubrie Rice
Rad Sci 4670
Literature Review
carbon ions.3 The study by Bassler and Jkel et al shows the benefits that could prevail from
using multi-modal radiation and LET-painting techniques with treatment. We could avoid
treating normal tissue with high-LET and increase high LET within hypoxic regions of the
tumor, therefore increasing tumor cell kill.
Another research article by Bassler and Toftegaard et al examines LET-painting with
carbon-12 and oxygen-16 ion treatments for a single oropharyngeal cancer case with a hypoxic
portion of the tumor.4 TRiP98, which is a treatment planning system used for heavy ion
radiotherapy, is used in this study.4 Planning target volume (PTV), gross target volume (GTV)
and hypoxic target volume (HTV) are identified in the treatment planning system.4 Two opposing
sets of fields were used to cover the PTV with a homogenous dose using carbon-12 ions.4 LETpainting or ramped fields were then compared with both carbon-12 and oxygen-16 ions.4 TRiP
was then able to return two voxel matrices with the dose distribution and the dose averaged
LET.4 From this, tumor control probability (TCP) could then be calculated.4 The study found
that LET-painting shows an improved tumor control probability and also that the use of LET
painting can cover irregular shaped areas inside the tumor.4 Bassler and Toftegaard et al also
found that the carbon-12 ions were only good for achieving tumor control with hypoxic
subvolumes that were smaller than 0.5 cm3.4 Oxygen-16 ions were found to be much more useful
with larger hypoxic subvolumes as large as 1 or 2 cm3.4
The last research article was a study conducted by Chang et al that examined the
effectiveness of using hypoxia targeted dose painting for head and neck cancer patients.5 A study
cohort was formed that consisted of eight patients with a primary diagnosis of squamous cell
carcinoma of the head and neck.5 All eight patients had PET CT scans prior to receiving radiation
therapy.5 The GTV, CTV and PTV were defined in the planning computer as well as the hypoxic
GTV (GTVH) or hypoxic subvolume within the GTV. Three PTVs were created, each having a 5
mm extension off each of the following: low risk CTV (PTV1), high risk CTV (PTV2), and GTV
(PTV3).5 A hypoxic PTV (PTVH) was then generated by adding a 3 mm margin to the GTVH.5
Seven or nine beam step and shoot IMRT plans were then created for these patients using
biologically based optimization.5 A total of three plans were created for each patient.5 The first
was a standard plan (STD) which had a simultaneous integrated boost with three dose levels: 56,
63 and 70 Gy to PTVs 1, 2 and 3, respectively. The second plan was a hypoxia dose painted plan

Aubrie Rice
Rad Sci 4670
Literature Review
(HDP) which consisted of the same dose levels as the STD but added another dose level: 84 Gy
to the PTVH. The third plan was a uniform dose escalation plan (UDE) which entailed dose
levels of 56, 63 and 84 Gy to PTVs 1, 2, and 3, respectively.5 Each treatment was planned to be
given in 35 fractions.5 The study used the Poisson TCP model to calculate the tumor control
probability (TCP).5 Target volume objectives were met in all 24 plans that were created. It was
found that UDE plans had the highest TCP with 94%, followed by HDP plans with 93% and then
STD plans with 73%. The mean normal tissue complication probability (NTCP) for the parotid
gland for each of the plans were found to be 26% (STD), 26% (HDP), and 44% (UDE), while
NTCP for the mandible was found to be 1% (STD), 2% (HDP), and 27% (UDE).5 From these
results, it is clear that while UDE plans had a higher tumor control probability, they also had
higher toxicity rates to normal structures such as the parotid gland and mandible. Based on the
results of Chang et al, HDP plans would improve therapeutic results since they had a high TCP
while maintaining low NTCPs with both the parotid and mandible.
Conclusion
The findings of these three studies by Bassler and Jkel et al3, Bassler and Toftegaard et
al4 and Chang et al5 show that LET painting, especially for hypoxic tumors, is a very promising
possible new feature for the radiotherapy world. First in 2010, Bassler and Jkel et al found that
by utilizing the high-LET portion of the SOBP, LET can be redistributed while maintaining a
similar dose distribution.3 This finding can mean increasing tumor cell-kill without increasing
normal tissue toxicity. Then in 2013 and 2014, studies by Chang et al and Bassler and Toftegaard
et al, respectively, showed further promising findings for LET painting.4,5 Bassler and Toftegaard
et al found that LET painting increased TCP for hypoxic portions of tumors and also found that
oxygen-16 ions were more useful with larger hypoxic subvolumes (1 2 cm3) when compared to
carbon-12 ions which were only beneficial to hypoxic subvolumes less than 0.5 cm3.4 The last
important find was by Chang et al which found that hypoxia dose painted (HDP) plans had high
tumor control while also maintaining low values of normal tissue toxicity compared to standard
plans for head and neck patients.5 The findings of these studies show that LET painting could be
very beneficial to cancer patients in the future.
Although results are promising, improvements could have been made to make these
studies more reliable. The study by Bassler and Jkel et al3 only compared two configurations

Aubrie Rice
Rad Sci 4670
Literature Review
and used a phantom for treatment planning. Better results could have been achieved with using
real patient CT or PET scans which would have provided realistic results. In this way, the study
by Chang et al5 was ideal, since they used CT and PET scans from eight head and neck cancer
patients and also compared three different treatment planning techniques. The study was limited
in the fact that it only had eight patients in the study. Having a larger study population would
have made the results more reliable. Although Bassler and Toftegaard et al4 used a real patient
plan, they only compared carbon and oxygen ions for a single patient. Having a larger study
group would give more valid results for this study as well.

References

Aubrie Rice
Rad Sci 4670
Literature Review
1. Barendsen GW, Koot CJ, Van Kersen GR, Bewley DK, Field SB, Parnell SB. The Effect of
Oxygen on Impairment of the Proliferative Capacity of Human Cells in Culture by Ionizing
Radiations of Different LET. Int J Radiat Biol Relat Stud Phys Chem Med. 1966;10(4):317-327.
2. Koh W, Griffin TW, Laramore GE, Stelzer KJ, Russell KJ. Fast Neutron Radiation Therapy:
Results of phase III randomized trials in head and neck, lung, and prostate cancers. Acta Oncol.
1994;33(3):293-298.
3. Bassler N, Jkel O, Sndergaard CS, Petersen JB. Dose- and LET-Painting with Particle
Therapy. Acta Oncol. 2010;49(7):1170-6.
4. Bassler N, Toftegaard J, Lhr A, Srensen BS, Scifoni E, Krmer M, Jkel O, Mortensen LS,
Overgaard J, Petersen JB. LET-Painting Increases Control Probability in Hypoxic Tumors. Acta
Oncol. 2014;53(1):25-32.
5. Chang JH, Wada M, Anderson NJ, Joon DL, Lee ST, Gong SJ, Gunawardana DH, Sachinidis
J, OKeefe G, Gan HK, Khoo V, Scott AM. Hypoxia-Targeted Radiotherapy Dose Painting for
Head and Neck Cancer Using (18)F-FMISO PET: A Biological Modeling Study. Acta Oncol.
2013;52(8):1723-9.