Intensity Modulated
Radiation Therapy:
The Analysis of Appropriate Usage versus
Associated Risks
Wes Zoller
12/2/2010
Introduction to Radiologic Technology 425
Introduction
Intensity modulated radiation therapy, also known as
IMRT, is an increasingly prevalent form of external beam
treatment in the field of radiation oncology. Utilizing multi-leaf
collimation—a series of motorized tungsten blocking plates—to
shape the treatment beam,1 IMRT is capable of sculpting fields to
deliver a maximum dose directly to the tumor site and
minimizing unwanted dosage to the surrounding organs. The
major contributor making this intensity modulated treatment
possible is the use of a treatment planning system, or TPS, that is
capable of formulating a plan based on certain inputs such as: 3D
target volume, dose distribution, dose plan objectives, and the
organs at risk.2 From these inputs, the planning system simulates
multiple iterations at different gantry angles until it ultimately
reaches the optimal balance between normal tissue avoidance and
target coverage. This type of planning—known as inverseplanning—can take considerably more time to formulate than
regular conventional treatment, and it typically involves multiple
intensities at multiple gantry angles.2
Due to the increased precision of this type of
radiotherapy, IMRT can allow for tumors to be treated to higher
doses and more fractions than conventional external beam
treatment would normally permit.3 The ability to give higher
dosage can be key in the success of radical treatment as more
tumor cells are destroyed, causing the likelihood of remission to
improve. As a direct result of this enhanced precision, the
possibility also exists to retreat patients with IMRT in a region of
the body that has already received dosage in a surrounding
proximity.3 With recurrent cancer cases, this can be an effective
way to extend a patient’s life.
Clinically, intensity modulated radiation therapy has
the potential to be of great assistance in certain treatments.
However, a real question exists as to when exactly the benefit is
worth the cost. Due to the increased planning time, computer
software, ranging intensity, and various gantry angles, IMRT is
significantly more expensive than conventional treatment—
approximately three times the price.1 As another concern, the
increased number of monitor units of radiation required due to
the collimation leaves allows for the possibility of leakage dose
to the patient.3 The large degree of gantry angles and delivery of
low dose exposures at each one have been hypothesized to lead to
secondary radiation-induced malignancies. Along with this, the
precision required for the treatment can be unreasonable for
anatomical areas where immobilization is difficult or organ
movement is frequent.3 As a treatment method, IMRT must be
evaluated based on its application to varying anatomical targets
as well as the potential to introduce unnecessary risk to patients.
In order to answer the question as to when its use is considered
appropriate, it is essential to examine the relative effectiveness of
IMRT for site-specific treatments when compared to
conventional radiotherapy as a control. In congruence, it is also
relevant to explore the reasons for and against increased usage.
Zoller 2
Review of Literature/Discussion
By looking at the effectiveness of IMRT to specific
sites when compared directly to conventional external beam
radiotherapy, the benefits of the treatment are capable of being
stacked against potential risk. In a recent article by Jean-Philippe
Pignol,4 the effectiveness of IMRT treatment on breast cancer is
compared to the control of conventional treatment. In areas of
separation, such as the inframammary fold beneath the breast,
there is a tendency to have overhang which can lead to scatter
radiation. Due to this scatter, it is quite likely that patients with
breast cancer experience high levels of skin irritation—
potentially moist desquamation—in this fold during conventional
breast treatment. In order to gain an understanding if this skin
toxicity can be avoided using IMRT capabilities, 331 women
with localized breast cancer were enrolled in a study performed
by two Canadian cancer centers between 2003 and 2005. 170 of
these patients received treatment using IMRT to conform the
beams to the shape of the tissue. As a control, 161 received two
conventional opposed tangent fields, which utilized wedges to
help shape the dosage to fit the curvature of the patient’s breast.
Patients were treated to 50 Gray over the course of 25 fractions.
Throughout the treatment, the patients visited with the
oncologists weekly, answering questions regarding the maximum
intensity of the treatment symptoms. During this, both the
oncologists and the patients were blinded as to which study arm
the patient was undergoing. After the treatment process, patients
had follow-ups 1, 2, 4, and 6 weeks post-completion to continue
the monitoring of skin side-effects. Patients also filled out
surveying questions regarding quality of life due to treatment, as
well as pain assessment. As a result, 47.8% of patients who
received conventional treatment showed moist desquamation
during or after radiotherapy as opposed to only 31.2% of the
patients who were treated using IMRT.
Based on the
questionnaires, patients experiencing moist desquamation at the
time of the survey showed a much higher pain score and a lower
quality of life score than those not experiencing this form of
radiodermatitis.4
At nearly a 17% difference in signs of moist
desquamation, IMRT showed to have a significant advantage in
avoidance of this type of skin toxicity. Along with this, the lower
quality of life score is significant as it shows that patients with
moist desquamation are experiencing more pain and believe that
they have a lower quality of living. The results here suggest that
IMRT has the potential to improve on this occurrence by
delivering a tissue saving dose to the breast. In accordance, it is
possible that patients will have an easier time going through
treatment if these skin irritation side-effects are minimized. From
this study, it appears IMRT could make breast treatment more
manageable for the patients—an indication that it could be the
standard of treatment when the breast target volume is small
enough. However, by spanning merely 331 patients across just
two cancer centers, the evidence of this study could greatly be
buttressed through a wider testing zone. More centers need to be
introduced, as well as participant numbers rising into the
thousands. It is quite possible that by using just two cancer
centers, it could be the same brain-trust of dosimetrists planning
the conventional fields. By introducing new linear accelerators
and new physicians to the treatment planning, the possibility of a
third variable can be put to rest. If IMRT is more advantageous
than conventional at treating localized breast cancer, a broader
study can only benefit in providing validity.
Along with breast treatment, another site-specific group
of carcinomas—head and neck—could be impacted through the
dose shaping capabilities of IMRT. This region can be very
difficult to deliver high doses of radiation to due to the presence
of several critical structures in the area such as the spinal cord,
the optical apparatus, the parotid glands, and the esophagus.2
Through the use of IMRT, it may be possible to reduce toxicity
and deliver greater dosages to specific sites in the head and neck.
In the Staffurth journal article,2 a PARSPORT study of 94
patients with cancer of the oropharynx and hypopharynx were
treated—half receiving inverse-planned IMRT treatment with the
other half receiving conventional external beam treatment. One
year after the conclusion of treatment, 74% of the patients treated
in the conventional arm possessed xerostomia—chronic dry
mouth due to scarring of the parotid glands—placed at grade 2 or
above. For the IMRT arm, only 40% showed xerostomia graded
at 2 or above at the end of one year.2 In support of this, Staffurth
combined and totaled the results of 15 non-randomized studies
that compared parotid-sparing IMRT treatment to conventional.
These patients had varying diagnoses contained to carcinoma of
the oral cavity, oropharygeal cancer, laryngeal cancer and
hypopharygeal cancer. In all, 959 participants were treated with
inverse-planning IMRT treatment, and 1455 received
conventional treatment as a control. Across the board, the IMRT
arm had lower levels of xerostomia, especially at12 months and
beyond. Due to the limitation of dose to the parotids and the
esophagus, many of the studies resulted in less pain, reduced
dysphagia, and improved eating in the IMRT patients. In
congruence, this was accompanied with a reduced need for longterm percutaneous endoscopic gastrostomy (PEG) feeding tube
placement. One study even showed improved one to two year
survival rates for patients receiving IMRT resulting from the
ability to increase dosage to the tumor site.2
Based on the numbers of patients ranging in the
thousands, the collection of studies appears to show the positive
effects of IMRT usage on the head and neck area. The reduced
xerostomia levels, specifically at one year and later, suggests that
IMRT treatment greatly reduces dosage to the parotid glands, and
it even allows for the function of the glands to come back to an
extent post treatment. As for esophagus involvement, it is vital to
avoid too much irritation to this area so the patients can eat food
without escalated pain. Anorexia and cachexia are both concerns
in head and neck patients. If IMRT, as this article suggests, can
improve the patient’s ability to eat without the long-term
insertion of a PEG tube, this could potentially lead to great results
in weight maintenance. Lastly, with the ability to deliver higher
doses to the tumor site without fear of toxicity to a critical
structure, it may be more likely for radical treatment to result in
1-2 year survivals. In fact, this study could be greatly benefited
by following the 5 and 10 year survival of these patients down
the line—perhaps even collecting a greater sample size by
monitoring more patients in this type of clinical study. After
these results are collected years later, it could be possible to
determine the actual impact of IMRT on recurrence and
remission rates when compared to conventional treatment.
With the benefits of this type of treatment, there are
also a few areas of concern. In order to deliver such high doses
to the target site, IMRT uses multiple gantry angles with varying
intensities that generate low dosages to a large portion of the
surrounding tissue. All of these beams collect at the isocenter to
create a total with great intensity. This method of centralizing
beam strength at the target may have disadvantages. According
to Eric Hall,5 this low dose of radiation exposure to the
surrounding tissue has the potential to create secondary radiationinduced malignancies. Based on information gathered from
atomic-bomb survivors, he suggests that a positive linear
Zoller 3
relationship exists between cancer incidence and dose from 0.1
sievert to 2.5 sievert. After the 2.5, Hall is uncertain of the
relationship between cancer and dose, but believes it has the
potential to begin to plateau. This is based on the idea that as
exposure increases, the introduction of transformed cells arises.
As the dose continues to increase, the radiation begins to kill
these transformed cells—thus creating a level off between cancer
introduction and cancerous cell destruction. Another area of
concern is the increased number of monitor units required for
IMRT treatment. Due to the multi-leaf collimation that blocks
out large beam portions, the monitor units must be increased in
order to deliver the proper amount of prescribed dose to the
patient. With these increased monitor units, the risk of leakage
radiation to the patient is high—with roughly 1-3% reaching the
patient as scatter to the total body. With these factors combined,
the author estimates that the risk of radiation-induced secondary
malignancies from IMRT is double that of conventional
treatment.5
Using surgical treatment as a control, the National
Cancer Institute of the United States predicts that external beam
therapy, at 10 years post-treatment, will lead to 1 in 70 patients
developing a radiation-induced malignancy.5 According to Hall,
this number could be doubled through IMRT and the benefit
would still be worth the risk. However, in the case of children,
he indicates that they are at least ten times more susceptible to
secondary tumors than their adult counterparts. This is due to
increased susceptibility to radiation due to growing tissue and a
smaller body size which can lead to greater effects of scatter.
Accompanying this, Hall claims that since the majority of
childhood cancers are genetically germline induced rather than
environmental, the children’s bodies are more susceptible to
secondary tumors via DNA mutation to begin with. Due to the
increased susceptibility, Hall questions the benefit when
compared to the risk in children.5
To gain a better understanding of low dose and high
dose radiation affects on tumor introduction, it would be
outstanding to conduct a research study that follows IMRT
treated patients against surgically treated patients. As a control,
treatment such as localized prostate cancer could be used due to
its ability to have positive surgical outcomes and remission.
However, the great difficulty in this study is the range of years
required to accrue such data—5-10 years at a minimum. Due to
the collimation-induced scatter and increased monitor units, it is
plausible that IMRT treatment doubles the rate of secondary
tumors when compared to conventional. Even so, 1 in 70 equates
to about 1.4%, which results in 2.8% when hypothetically
doubled through IMRT. Based on the benefits in certain
anatomical areas, as discussed, this small percentage is still
insignificant in comparison to benefit. Hypothetically assuming
that children have 10 times the risk of radiation-induced
secondary malignancies, this would indicate that at a minimum,
the risk would go from 14% to 28% by using IMRT in children.
This is a significant risk, and the cost-benefit analysis would be
highly based on the prognosis of the child, as well as the
increased efficacy of IMRT over conventional for the anatomical
site.
Due to the dose intensity and small target volumes of
IMRT treatment, daily repetition and precision are more
difficulties in its usage as a standard treatment. According the
Karol Sikora,1 intensity modulated radiation therapy is nearly
always coupled with image guidance to assist in the process of
alignment. These methods include the use of mV x-rays taken
with the linear accelerator, as well as separate attachments that
allow for kV x-rays and cone-beam computed tomography for
anatomical viewing.1
This procedure seems to be very
manageable, and allows for patients to be placed very
repetitively. However, these port x-rays and CT’s are often done
daily or weekly throughout treatment. They are extra expenses
for the patient, not to mention expose him or her to extra doses of
ionizing radiation. The kV image guidance equipment provides
greater resolution than the mV images which assists in precision
set-up—however, they also tend to give a higher dose near the
surface of the skin. Often times, external beam patients are
already having skin irritation from treatment—any more could
lead to greater toxicity. Certainly, these are things to think about
when determining if the precision required for IMRT is worth its
benefit as the treatment choice.
Sometimes, even image guidance is not enough to align
a patient in an area that suits intensity modulated radiation
therapy. As Dr. Loren Mell points out,3 IMRT treats patients
with very high dose gradients in close proximity to the borders of
the planned target volume. Along with this, the margin between
the planned target and the actual clinical target is less for IMRT
than conventional radiotherapy. Some anatomical areas of the
body such as the abdomen and chest are partially mobile
throughout treatment, which suggests that the tumor could shift
outside of the dose gradient and not receive enough radiation
exposure to properly exterminate the malignant cells. Along with
this, IMRT is typically used to treat around critical structures due
to its ability to shape intensity. Any slight movement could
introduce a critical structure into the high dose field, potentially
causing detrimental toxicity.
In Mell’s article,3 two studies that surveyed oncologists
regarding the use of IMRT were evaluated . The first was
conducted in 2002 and randomly selected 450 physicians from
the American Society of Therapeutic Radiology and Oncology
(ASTRO) directory. The second was done in 2004, utilizing the
same directory and selecting 500 physicians—93 being the same
from the 2002 survey. Both surveys asked the same questions,
basically asking if the physician utilizes IMRT, and his or her
main reasons for doing so. The study showed that in 2002, 32%
were using IMRT treatment, with that number sky-rocketing to
73.2% in 2004 . Also noted in the 2004 study was the statistic
that of those who did not use IMRT at the time of questioning,
90.6% said that they planned to in the future. Based on the 2004
study, the main reasons listed for the adoption of intensity
modulated radiation therapy were its abilities to spare normal
tissues, where 88% listed it as one of the reasons, and to give
higher doses than conventional—specifically to the head and
neck—at 85.1%. However, 49.1% of the respondents claimed
that they used IMRT to remain competitive with other cancer
centers, and 29.5% admitted to using it to gain a competitive
advantage. According to Mell, the increased prevalence and
knowledge of IMRT creates pressure for many cancer centers to
adopt it into practice. Along with this, these last two statistics
indicate that economic incentive could raise questions regarding
ethical practice and this increasing usage of IMRT.3 In 2009, the
Institute of Clinical and Economic Review in the USA
determined that IMRT prostate treatment costs approximately
$42,450 per course as opposed to just $10,900 for conventional
prostate treatment.2
In these studies, approximately 35% of the physicians
did not respond to the survey.3 Also, due to the aged dating of the
studies, it would be very useful to perform a similar one again in
the current year to evaluate the progression and reasons for
performing IMRT. Utilizing the ASTRO directory is sufficient,
Zoller 4
yet it may be better to include a larger sample than 450-500
participants in order to gain a more accurate conclusion.
Regardless, the increased usage of IMRT is clearly evident, and
the reasons for doing so speak to the dose shaping and tissue
sparing capabilities of this type of treatment. However, the
economic concern and the confession of competitiveness and
gaining an edge as motivation for many participants bode
particularly alarming for the present. Ethical usage is a key
factor with IMRT, as it must be used when it is advantageous and
appropriate for the patient.
Conclusion
Based on clinical evidence, IMRT at the very least has
the potential to treat tumors to higher doses and around more
critical structures than its conventional counterpart. This can be
particularly valuable for patients who are being retreated with
surrounding radiation-scarred organs as well as for impingements
of particular critical structures such as the spinal cord. With
IMRT, it is plausible that curative treatment can be more
successful in some areas of the body, such as the head and neck
where higher dosage provides a better chance of killing the
malignant cells. Using multiple fields through inverse-planning,
the tissue can also be spared, such as in the treatment of breast
cancer. In these cases that provide better patient outcomes, the
benefit could show to be worth the risk.
Using economic gain and competitive advantage as the
sole reasons for selecting IMRT treatment over conventional
could put a patient in danger. Due to leakage radiation exposure
and the hypothesized risk of secondary malignancies, some
patients will not benefit if the situation does not distinctively
permit for IMRT. In children, this is especially an area of interest
as they are believed to be very susceptible to radiation and
possess an increased propensity of developing radiation-induced
tumors from treatment. Also, certain areas of the body where
motion is at a premium, such as the lungs and abdomen, need to
be evaluated prior to treatment to determine the best course of
action for the patient. When it comes to health care, the radiation
oncologist’s job is to look after the well-being of the patient at all
times.
This is especially true when deciding to use IMRT
treatment. Certainly, the advantages are useful in many cases,
but in other instances, conventional treatment can be just as
effective while reducing several risks that could potentially be
associated with IMRT. With time, more clinical studies will
present themselves, and it will be easier to draw a definitive line
for the appropriate usage of intensity modulated radiation
therapy. For now, the prognosis, tumor site, and age of the
patient need to be evaluated thoroughly in order to understand the
situational risks and benefits for providing the best chance for
successful outcomes.
References
1)
Sikora K et al. Precision radiotherapy: a guide to
commissioning IMRT and IGRT. J. Management &
Marketing in Healthcare. November 2009;2:401-409.
2)
Staffurth J. A review of the clinical evidence for
intensity-modulated radiotherapy. Clinical Oncology.
23 June 2010; 22:643-657.
3)
Mell L, Mehrotra A, Mundt A. Intensity-modulated
radiation therapy use in the U.S., 2004. Cancer.
2005;104:1296–1303.
4)
Pignol J et al. A multicenter randomized trial of breast
intensity-modulated radiation therapy to reduce acute
radiation dermatitis. J. Clinical Oncology. May 1,
2008;58:2085-2092.
5)
Hall E. Intensity-modulated radiation therapy, proton,
and the risk of second cancers. Int. J. Radiation
Oncology Biol. Phys. 2006;65:1–7.