Download Intensity Modulated Radiation Therapy (IMRT) and Real

MEDICAL POLICY
POLICY TITLE
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
POLICY NUMBER
Original Issue Date (Created):
November 20, 2006
Most Recent Review Date (Revised):
September 30, 2014
Effective Date:
January 1, 2015- RETIRED*
POLICY
RATIONALE
DISCLAIMER
POLICY HISTORY
PRODUCT VARIATIONS
DEFINITIONS
CODING INFORMATION
DESCRIPTION/BACKGROUND
BENEFIT VARIATIONS
REFERENCES
*National Imaging Associates (NIA) Notice: This policy is retired as of the listed date. Policy is maintained
here to address services obtained prior to the retirement date. Current policies surrounding these
services are maintained with our vendor, National Imaging Associates (NIA) www.1.Radmd.com.
Please follow link for further information for services obtained after the retirement date.
I.
POLICY
Head and Neck Cancers
Intensity-modulated radiation therapy may be considered medically necessary for the
treatment of head and neck cancers.
Intensity-modulated radiation therapy may be considered medically necessary for the
treatment of thyroid cancers in close proximity to organs at risk (esophagus, salivary
glands, and spinal cord) and 3-D CRT planning is not able to meet dose volume constraints
for normal tissue tolerance. (See Policy Guidelines)
Policy Guidelines for Head and Neck Cancers
For this policy, head and neck cancers are cancers arising from the oral cavity and lip,
larynx, hypopharynx, oropharynx, nasopharynx, paranasal sinuses and nasal cavity,
salivary glands, and occult primaries in the head and neck region.
Organs at risk are defined as normal tissues whose radiation sensitivity may significantly
influence treatment planning and/or prescribed radiation dose. These organs at risk may be
particularly vulnerable to clinically important complications from radiation toxicity.
The following table outlines radiation doses that are generally considered tolerance
thresholds for these normal structures in the area of the thyroid.
Radiation Tolerance Doses for Normal Tissues
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
POLICY NUMBER
TD 5/5 (Gy)a
TD 50/5 (Gy)b
Portion of organ
involved
Portion of organ
involved
Site
1/3
2/3
3/3
1/3
2/3
3/3
Complicatio
n End Point
Esophagus
60
58
55
72
70
68
Stricture,
perforation
Salivary
glands
32
32
32
46
46
46
Xerostomia
Spinal cord
50
(510
cm)
NP
47
(20
cm)
NP
NP
70
(510
cm
)
Myelitis,
Breast and Lung Cancers
IMRT Breast
Intensity-modulated radiation therapy (IMRT) may be considered medically necessary as
a technique to deliver whole breast irradiation in patients receiving treatment for left-sided
breast cancer after breast-conserving surgery when all the following conditions have been
met:

Significant cardiac radiation exposure cannot be avoided using alternative radiation
techniques

IMRT dosimetry demonstrates significantly reduced cardiac target volume radiation
exposure. (See Policy Guidelines)
Intensity-modulated radiation therapy (IMRT) may be considered medically necessary in
individuals with large breasts when treatment planning with 3D conformal results in hot
spots (focal regions with dose variation greater than 10% of target) and the hot spots are
able to be avoided with IMRT. (See Policy Guidelines)
Intensity modulated radiation therapy (IMRT) of the breast is considered investigational as
a technique of partial breast irradiation after breast-conserving surgery. There is
insufficient evidence to support a conclusion concerning the health outcomes or benefits
associated with this procedure.
Intensity modulated radiation therapy (IMRT) of the chest wall is considered
investigational as a technique of postmastectomy irradiation. There is insufficient
evidence to support a conclusion concerning the health outcomes or benefits associated
with this procedure.
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Policy Guidelines for IMRT of the Breast
The following are an example of clinical guidelines that may be used with IMRT in leftsided breast lesions:


The target volume coverage results in cardiac radiation exposure that is expected
to be greater than or equal to 25 Gy to 10 cc or more of the heart (V25 greater
than or equal to 10 cc) with 3D conformal RT despite the use of a complex
positioning device (such as Vac-Lok™), and
with the use of IMRT, there is a reduction in the absolute heart volume receiving
25 Gy or higher by at least 20% (e.g., volume predicted to receive 25 Gy by 3D
RT is 20 cc and the volume predicted by IMRT is 16 cc or less).
The following are examples of criteria to define large breast size when using IMRT to
avoid hot spots, as derived from randomized studies:


Donovan and colleagues (1) enrolled patients with ‘higher than average risk of
late radiotherapy-adverse effects’, which included patients having larger breasts.
The authors state that while breast size is not particularly good at identifying
women with dose inhomogeneity falling outside current International
Commission on Radiation Units and Measurements guidelines, they excluded
women with small breasts (less than or equal to 500 cc), who generally have fairly
good dosimetry with standard 2D compensators.
In the trial by Pignol and colleagues, (2) which reported that the use of IMRT
significantly reduced the proportion of patients experiencing moist desquamation,
breast size was categorized as small, medium or large by cup size. Multivariate
analysis found that smaller breast size was significantly associated with a
decreased risk of moist desquamation (p less than .001).
IMRT –Lung
Intensity-modulated radiation therapy (IMRT) may be considered medically necessary as
a technique to deliver radiation therapy in patients with lung cancer when all of the
following conditions are met:

Radiation therapy is being given with curative intent

3D conformal will expose >35% of normal lung tissue to more than 20 Gy dosevolume (V20)

IMRT dosimetry demonstrates reduction in the V20 to at least 10% below the V20
that is achieved with the 3D plan (e.g. from 40% down to 30% or lower)
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Intensity-modulated radiation therapy (IMRT) is considered not medically necessary as a
technique to deliver radiation therapy in patients receiving palliative treatment for lung
cancer.
Policy Guidelines IMRT Breast and Lung
The following is an example of clinical guidelines that may be used with IMRT in leftsided breast lesions:

The target volume coverage results in cardiac radiation exposure that is expected to
be greater than or equal to 25 Gy to 10 cc or more of the heart (V25 greater than or
equal to 10 cc) with 3D conformal RT, despite the use of a complex positioning
device (such as Vac-Lok™), and

with the use of IMRT, there is a reduction in the absolute heart volume receiving 25
Gy or higher by at least 20% (e.g., volume predicted to receive 25 Gy by 3D RT is
20 cc and the volume predicted by IMRT is 16 cc or less).
The following are examples of criteria to define large breast size when using IMRT to
avoid hot spots, as derived from randomized studies:

Donovan and colleagues (1) enrolled patients with ‘higher than average risk of late
radiotherapy-adverse effects’, which included patients having larger breasts. The
authors state that while breast size is not particularly good at identifying women
with dose inhomogeneity falling outside current International Commission on
Radiation Units and Measurements guidelines, they excluded women with small
breasts (less than or equal to 500 cc), who generally have fairly good dosimetry
with standard 2D compensators.

In the trial by Pignol and colleagues, (2) which reported that the use of IMRT
significantly reduced the proportion of patients experiencing moist desquamation,
breast size was categorized as small, medium or large by cup size. Multivariate
analysis found that smaller breast size was significantly associated with a decreased
risk of moist desquamation (p less than .001).
Abdomen and Pelvis
Intensity modulated radiation therapy may be considered medically necessary as an
approach to delivering radiation therapy for patients with cancer of the anus/anal canal.
When dosimetric planning with standard 3-D conformal radiation predicts that the radiation
dose to an adjacent organ would result in unacceptable normal tissue toxicity (see Policy
Guidelines), intensity-modulated radiation therapy (IMRT) may be considered medically
necessary for the treatment of cancer of the abdomen and pelvis, including but not limited
to:

stomach (gastric);
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
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POLICY NUMBER

hepatobiliary tract;

pancreas;

rectal locations; or

gynecologic tumors (including cervical, endometrial, and vulvar cancers).
Intensity-modulated radiation therapy (IMRT) would be considered investigational for all
other uses in the abdomen and pelvis. There is insufficient evidence to support a conclusion
concerning the health outcomes or benefits associated with this procedure for these
indications
Policy Guidelines for IMRT of the Abdomen and Pelvis Radiation tolerance doses for
normal tissues of the abdomen and pelvis
TD 5/5 (Gy)a
TD 50/5 (Gy)b
Portion of organ
involved
Portion of organ
involved
Site
1/3
2/3
Heart
60
45
Lung
45
30
Spinal
cord
50
50
Kidne
y
50
30
Liver
50
35
Stoma
ch
60
55
3/3
40
17.5
47
23
30
50
1/3
2/3
70
55
65
40
70
70
NP
40
55
45
70
67
3/3
Complication
endpoint
50
Pericarditis
24.5
Pneumonitis
NP
Myelitis/necrosis
28
Clinical nephritis
40
Liver failure
65
Ulceration/perforatio
n
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
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POLICY NUMBER
Small
intesti
ne
50
NP
Femor
al head
NP
NP
40
52
60
NP
NP
NP
55
Obstruction/perforati
on
65
Necrosis
aTD 5/5, the average dose that results in a 5% complication risk within 5 years
bTD 50/5, the average dose that results in a 50% complication risk within 5 years
NP: not provided
The tolerance doses in the table are a compilation from the following two sources:
Morgan MA (2011). Radiation Oncology. In DeVita, Lawrence and Rosenberg, Cancer
(p.308). Philadelphia: Lippincott Williams and Wilkins.
Kehwar TS, Sharma SC. Use of normal tissue tolerance doses into linear quadratic
equation to estimate normal tissue complication probability.
http://www.rooj.com/Radiation%20Tissue%20Tolerance.htm
In order for IMRT to provide outcomes that are superior to 3DCRT, there must be a
clinically meaningful decrease in the radiation exposure to normal structures with IMRT
compared to 3DCRT. There is not a standardized definition for a clinically meaningful
decrease in radiation dose. In principle, a clinically meaningful decrease would signify a
significant reduction in anticipated complications of radiation exposure. In order to
document a clinically meaningful reduction in dose, dosimetry planning studies should
demonstrate a significant decrease in the maximum dose of radiation delivered per unit of
tissue, and/or a significant decrease in the volume of normal tissue exposed to potentially
toxic radiation doses. While radiation tolerance dose levels for normal tissues are wellestablished, the decrease in the volume of tissue exposed that is needed to provide a
clinically meaningful benefit has not been standardized. Therefore, precise parameters for a
clinically meaningful decrease cannot be provided.
Prostate Cancer
Intensity modulated radiation therapy (IMRT) may be considered medically necessary in
the primary treatment of localized prostate cancer at radiation doses of 75 to 80Gy.
Central Nervous System Tumors
Intensity-modulated radiation therapy (IMRT) may be considered medically necessary for
the treatment of tumors of the central nervous system when the tumor is in close proximity
to organs at risk (brain stem, spinal cord, cochlea and eye structures including optic nerve
and chiasm, lens and retina) and 3-D CRT planning is not able to meet dose volume
constraints for normal tissue tolerance. (See Policy Guidelines)
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Policy Guidelines CNS
Organs at risk are defined as normal tissues whose radiation sensitivity may significantly
influence treatment planning and/or prescribed radiation dose. These organs at risk may be
particularly vulnerable to clinically important complications from radiation toxicity.
Radiation tolerance doses for normal tissues
TD 5/5 (Gy) a
TD 50/5 (Gy) b
Portion of organ involved
Portion of organ
involved
Site
1/3
1/3
Brain stem
2/3 3/3
Complication End
Point
60
53 50
NP
50 (5-10 cm)
47 (20 cm)
NP
70 (5-10 cm)
NP 65
Necrosis, infarct
50
50
50
65
65
65
Blindness
Retina
45
45
45
65
65
65
Blindness
Eye lens
10
10
10
18
18
18
Cataract requiring intervention
Spinal cord
Optic nerve and chiasm
2/3 3/3
NP NP Myelitis, necrosis
Radiation tolerance doses for the cochlea have been reported to be 50 Gy
a
TD 5/5, the average dose that results in a 5% complication risk within 5 years
b
TD 50/5, the average dose that results in a 50% complication risk within 5 years
NP: not provided
cm=centimeters
The tolerance doses in the table are a compilation from the following two sources:
Morgan MA (2011). Radiation Oncology. In DeVita, Lawrence and Rosenberg, Cancer (p.308).
Philadelphia: Lippincott Williams and Wilkins.
Kehwar TS, Sharma SC. Use of normal tissue tolerance doses into linear quadratic equation to
estimate normal tissue complication probability. http://www.rooj.com/Radiation%20Tissue%20Tolerance.htm
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Real-Time Intra-Fraction Target Tracking During Radiation Therapy
Real-time intra-fraction target tracking during radiation therapy to adjust radiation doses or
monitor target movement during individual radiation therapy treatment sessions is considered
not medically necessary.
II.
PRODUCT VARIATIONS
Top
[N] = No product variation, policy applies as stated
[Y] = Standard product coverage varies from application of this policy, see below
[N] Capital Cares 4 Kids
[N] Indemnity
[N] PPO
[N] SpecialCare
[N] HMO
[N] POS
[N] SeniorBlue HMO*
[Y] FEP PPO**
[N] SeniorBlue PPO*
** Refer to FEP Medical Policy Manual for the following policies:
MP-2.03.10 Real-Time Intra-Fraction Target Tracking During Radiation Therapy.
MP-8.01.46 Intensity Modulated Radiation Therapy (IMRT) of the Lung
MP-8.01.48 Intensity Modulated Radiation Therapy (IMRT) Cancer of the Thyroid
MP-8.01.49 Intensity Modulated Radiation Therapy (IMRT) Abdomen and Pelvis
MP-8.01.59 Intensity Modulated Radiation Therapy (IMRT) CNS Tumors
The FEP Medical Policy manual can be found at: www.fepblue.org
Note: Effective July 1, 2010, FEP no longer requires pre-auth for outpatient IMRT
provided for the treatment of head, neck, breast, or prostate cancer.
III. DESCRIPTION/BACKGROUND
Top
Radiation therapy is an integral component in the treatment of breast and lung cancers.
Intensity modulated radiation therapy (IMRT) has been proposed as a method of radiation
therapy that allows adequate radiation therapy to the tumor while minimizing the
radiation dose to surrounding normal tissues and critical structures.
For certain stages of many cancers, including breast and lung, randomized clinical trials
have shown that postoperative radiation therapy improves outcomes for operable patients.
Adding radiation to chemotherapy also improves outcomes for those with inoperable lung
tumors that have not metastasized beyond regional lymph nodes.
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Radiation techniques
Conventional external-beam radiation therapy. Over the past several decades, methods to
plan and deliver radiation therapy have evolved in ways that permit more precise
targeting of tumors with complex geometries. Most early trials used 2-dimensional
treatment planning, based on flat images and radiation beams with cross-sections of
uniform intensity that were sequentially aimed at the tumor along 2 or 3 intersecting axes.
Collectively, these methods are termed “conventional external beam radiation therapy”.
3-dimensional conformal radiation (3D-CRT). Treatment planning evolved by using 3dimensional images, usually from computed tomography (CT) scans, to delineate the
boundaries of the tumor and discriminate tumor tissue from adjacent normal tissue and
nearby organs at risk for radiation damage. Computer algorithms were developed to
estimate cumulative radiation dose delivered to each volume of interest by summing the
contribution from each shaped beam. Methods also were developed to position the patient
and the radiation portal reproducibly for each fraction and immobilize the patient, thus
maintaining consistent beam axes across treatment sessions. Collectively, these methods
are termed 3-dimensional conformal radiation therapy (3D-CRT).
Intensity-modulated radiation therapy (IMRT). IMRT, which uses computer software, CT
images, and magnetic resonance imaging (MRI), offers better conformality than 3D-CRT
as it is able to modulate the intensity of the overlapping radiation beams projected on the
target and to use multiple-shaped treatment fields. It uses a device (a multileaf collimator,
MLC) which, coupled to a computer algorithm, allows for “inverse” treatment planning.
The radiation oncologist delineates the target on each slice of a CT scan and specifies the
target’s prescribed radiation dose, acceptable limits of dose heterogeneity within the
target volume, adjacent normal tissue volumes to avoid, and acceptable dose limits within
the normal tissues. Based on these parameters and a digitally reconstructed radiographic
image of the tumor and surrounding tissues and organs at risk, computer software
optimizes the location, shape, and intensities of the beams ports, to achieve the treatment
plan’s goals.
Increased conformality may permit escalated tumor doses without increasing normal
tissue toxicity and thus may improve local tumor control, with decreased exposure to
surrounding normal tissues, potentially reducing acute and late radiation toxicities. Better
dose homogeneity within the target may also improve local tumor control by avoiding
underdosing within the tumor and may decrease toxicity by avoiding overdosing.
Since most tumors move as patients breathe, dosimetry with stationary targets may not
accurately reflect doses delivered within target volumes and adjacent tissues in patients.
Furthermore, treatment planning and delivery are more complex, time-consuming, and
labor-intensive for IMRT than for 3D-CRT. Thus, clinical studies must test whether
IMRT improves tumor control or reduces acute and late toxicities when compared with
3D-CRT.
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Methodologic issues with IMRT studies
Multiple-dose planning studies have generated 3D-CRT and IMRT treatment plans from
the same scans, then compared predicted dose distributions within the target and in
adjacent organs at risk. Results of such planning studies show that IMRT improves on
3D-CRT with respect to conformality to, and dose homogeneity within, the target.
Dosimetry using stationary targets generally confirms these predictions. Thus, radiation
oncologists hypothesized that IMRT may improve treatment outcomes compared with
those of 3D-CRT. However, these types of studies offer indirect evidence on treatment
benefit from IMRT, and it is difficult to relate results of dosing studies to actual effects
on health outcomes.
Comparative studies of radiation-induced side effects from IMRT versus alternative
radiation delivery are probably the most important type of evidence in establishing the
benefit of IMRT. Such studies would answer the question of whether the theoretical
benefit of IMRT in sparing normal tissue translates into real health outcomes. Single-arm
series of IMRT can give some insights into the potential for benefit, particularly if an
adverse effect that is expected to occur at high rates is shown to decrease by a large
amount. Studies of treatment benefit are also important to establish that IMRT is at least
as good as other types of delivery, but in the absence of such comparative trials, it is
likely that benefit from IMRT is at least as good as with other types of delivery.
Regulatory Status
The U.S. Food and Drug Administration (FDA) has approved a number of devices for use
in intensity-modulated radiation therapy (IMRT), including several linear accelerators
and multileaf collimators. Examples of approved devices and systems are the NOMOS
Slit Collimator (BEAK™) (NOMOS Corp.), the Peacock™ System (NOMOS Corp.), the
Varian Multileaf Collimator with dynamic arc therapy feature (Varian Oncology
Systems), the Saturne Multileaf Collimator (GE Medical Systems), the Mitsubishi 120
Leaf Multileaf Collimator (Mitsubishi Electronics America Inc.), the Stryker Leibinger
Motorized Micro Multileaf Collimator (Stryker Leibinger), the Mini Multileaf
Collimator, model KMI (MRC Systems GMBH), and the Preference® IMRT Treatment
Planning Module (Northwest Medical Physics Equipment Inc.).
This policy addresses IMRT indications for the head and neck, abdomen and pelvis,
prostate, breast and lung and central nervous system.
Real-Time Intra-Fraction Target Tracking During Radiation Therapy
These techniques enable adjustment of the target radiation while it is being delivered (i.e.,
intra-fraction adjustments) to compensate for movement of the organ inside the body.
Real-time tracking, which may or may not use radiographic images, is one of many
techniques referred to as “image-guided radiation therapy” (IGRT). For this policy realtime tracking is defined as frequent or continuous target tracking in the treatment room
during radiation therapy, with periodic or continuous adjustment to targeting made on the
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
basis of target motion detected by the tracking system. This policy does not address
approaches used to optimize consistency of patient positioning in setting up either the
overall treatment plan or individual treatment sessions (i.e., inter-fraction adjustments),
instead it deals with approaches to monitor target movement within a single treatment
session. This policy will also not address technologies using respiratory gating.
In general, intra-fraction adjustments can be grouped into two categories: online and offline. An online correction occurs when corrections or actions occur at the time of
radiation delivery on the basis of predefined thresholds. An offline approach refers to
target tracking without immediate intervention.
During radiation therapy, it is important to target the tumor so that radiation treatment is
delivered to the tumor but surrounding tissue is spared. This targeting seems increasingly
important as dose-escalation is used in an attempt to improve long-term tumor control
and improve patient survival. Over time, a number of approaches have evolved to
improve targeting of the radiation dose. Better targeting has been achieved through
various approaches to radiation therapy, such as 3-D conformal treatment and intensitymodulated radiation therapy (IMRT). For prostate cancer, use of a rectal balloon has been
reported to improve consistent positioning of the prostate and thus reduce rectal tissue
irradiation during radiation therapy treatment of prostate cancer. In addition, more
sophisticated imaging techniques, including use of implanted fiducial markers, has been
used to better position the tumor (patient) as part of treatment planning and individual
radiation treatment sessions.
Intra-fraction target motion can be caused by many things including breathing, cardiac
and bowel motion, swallowing or sneezing. Data also suggests that a strong relationship
may exist between obesity and organ shift, indicating that without some form of target
tracking, the target volume may not receive the intended dose for patients who are
moderately to severely obese.
As noted above, the next step in this evolving process of improved targeting is the use of
devices to track the target (tumor motion) during radiation treatment sessions and allow
adjustment of the radiation dose during a session based on tumor movement. While not
an exhaustive list, examples of some U.S. Food and Drug Administration (FDA) cleared
devices are listed in the following section. Some of the devices are referred to as “4-D
imaging.” One such device is the Calypso® 4D Localization System. This system uses a
group of 3 electromagnetic transponders (Beacon®) implanted in the prostate to allow
continuous localization of a treatment isocenter. The transponders are 8.5 mm long and
have a diameter of 1.85 mm. The 3 transponders have a “field of view” of 14-cm square
with a depth of 27 cm.
The Calypso 4D localization system obtained FDA clearance for prostate cancer in
March 2006 through the 510(k) process (K060906). This system was considered
equivalent to existing devices such as implanted fiducials.
Another system, the Cyberknife® Robotic Radiosurgery System, is a computercontrolled medical system for planning and performing image-guided stereotactic
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radiosurgery and precision radiotherapy. This system uses gold fiducials implanted in the
prostate first to determine the absolute position of the target location, then to track 3dimensional translation and rotation deviation from that location during treatment.
During treatment, the computer automatically adjusts the incident beam to compensate
for target deviation. While the system can compensate for deviations of 10 mm, the larger
the deviation, the greater is the uncertainty in the computer correction.
The Cyberknife Robotic Radiosurgery System obtained FDA clearance in September
2007 through the 510(k) process (K072504) for any location in the body when radiation
therapy is indicated. This system was considered equivalent to existing devices.
IV. RATIONALE
Top
Real-Time Intra-Fraction Target Tracking During Radiation Therapy
Randomized trial data are needed to show the impact on clinical outcomes of real-time
tracking devices that allow for adjustments during radiation therapy or monitor the tumor
target during individual treatment sessions. The clinical outcomes could be disease
control (patient survival) and/or toxicity (e.g., less damage to adjacent normal tissue).
Since intensity-modulated radiation therapy (IMRT) and IMRT plus real-time tracking
are likely to produce equivalent therapeutic results, given the increased cost of real-time
tracking, the technique (tracking) needs to demonstrate incremental clinical benefit over
IMRT. To date, clinical outcome studies have not been reported for any tumor site but
will be required to show that target tracking during radiotherapy leads to a clinically
meaningful change in outcomes. The majority of the work in this evolving area is in
prostate cancer, although there are also studies of the technique in other organs such as
lung and breast.
Studies have focused on movement of the target during radiation therapy sessions. This is
considered an initial step in evaluating this technology but is not sufficient to determine if
patient outcomes are improved. As Dawson and Jaffray comment, the clinically
meaningful thresholds for target tracking and re-planning of treatment during a course of
radiation therapy are not yet known. (2) Even less is known about the impact of target
tracking within a single treatment session.
These new devices do appear to provide accurate localization. Santanam and colleagues
reported on the localization accuracy of electromagnetic tracking systems and on-board
imaging systems. (3) In this study, both the imaging system and the electromagnetic
system showed submillimeter accuracy during a study of both a phantom and a canine
model. Kindblom et al. similarly showed electromagnetic tracking was feasible with the
Micropos transponder system and that the accuracy of transponder localization was
comparable to x-ray localization of radiopaque markers. (4) Smith et al. successfully
coupled an electromagnetic tracking system with linear accelerator gating for lung
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cancer. (5) A currently registered trial is looking at the movement of the cervix during
radiation therapy.
Literature Review
In a retrospective analysis of data collected from the treatment of 21 patients with
prostate cancer treated with Cyberknife, Xie et al. reported on the intra-fractional
movement of the prostate during hypofractionated radiotherapy.(6) The analysis included
427 datasets composed of the time it took for the prostate to move beyond an acceptable
level (approximately 5 mm). The data suggest that it takes approximately 697 seconds for
the prostate to move beyond 5 mm relative to its planned position and that motion of
greater than 2 mm at 30 seconds was present in approximately 5% of datasets. The
percentage increases to 8%, 11%, and 14% at 60, 90, and 120 seconds, respectively. They
concluded that these movements could be easily managed with a combination of manual
couch movements and adjustment by the robotic arm. As noted earlier, the clinical impact
of these displacements and resultant adjustments in treatments needs to be explored in
much greater detail.
Noel et al. published data showing that intermittent target tracking is more sensitive than
pre- and post-treatment target tracking to assess intra-fraction prostate motion, but to
reach sufficient sensitivity, intermittent imaging must be performed at a high sampling
rate. (7) They concluded that this supports the value of continuous real-time tracking.
While this may be true, there is a major gap in the literature addressing the actual
consequences of organ motion during radiation therapy. Li and colleagues analyzed data
from 1,267 tracking sessions from 35 patients to look at the dosimetric consequences on
intra-fraction organ motion during radiation therapy. (8) Results showed that even for the
patients showing the largest overall movement, the prostate uniform equivalent dose was
reduced by only 0.23%, and the minimum prostate dose remained over 95% of the
nominal dose. When margins of 2 mm were used, the equivalent uniform dose was
reduced by 0.51%, but sparing of the rectum and bladder was significantly reduced using
the smaller margins. This study did not report on clinical outcomes, and data from a
larger randomized cohort will be needed to verify these results.
Sandler and colleagues reported on 64 patients treated with IMRT for prostate cancer in
the Assessing the Impact of Margin Reduction (AIM) study. (9) Patients were implanted
with Beacon transponders (Calypso Medical Technologies, Inc., Seattle, WA) and were
treated with IMRT to a nominal dose of 81 Gy in 1.8 Gy fractions. Patients in this study
were treated with reduced tumor margins, as well as real-time tumor tracking. Patientreported morbidity associated with radiotherapy was the primary outcome. Study
participants were compared to historic controls. Study participants reported fewer
treatment-related symptoms and/or worsening of symptoms after treatment than the
comparison group. For example, the percentage of patients in the historic comparison
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group reporting rectal urgency increased from 3% pre-treatment to 22% post-treatment,
no increase was observed in the current experimental group.
In a clinical study, Kupelian et al. described differences found in radiation therapy
sessions performed on 35 patients with prostate cancer. (10) In this paper, 6 of the initial
41 patients could not be studied because body habitus (A-P dimension) was too large to
allow imaging. The results showed good agreement with x-ray localization.
Displacements of 3 mm or more and 5 mm or more for cumulative duration of at least 30
seconds were observed during 41% and 15% of radiation sessions, respectively. The
clinical sites for the study developed individualized protocols for responding to observed
intra-fraction motion. This publication did not report on clinical implications or clinical
outcomes, either for control of disease or treatment complications, e.g., proctitis. The
clinical impact of these displacements and resultant adjustments in treatments needs to be
explored in much greater detail.
Langen and colleagues reported on 17 patients treated at one of the centers in the study
noted in the preceding paragraph. (11) In this study, overall, the prostate was displaced
by greater than 3 mm in 13.6% of treatment time and by greater than 5 mm in 3.3% of
treatment time. Results for median treatment time instead of mean were 10.5% and 2.0%,
respectively. Again, the clinical impact of this movement was not determined. The
authors did comment that potential clinical impact would depend on a number of factors
including the clinical target volume (CTV). In this small series, intra-fraction movement
did not change a large degree during treatment. However, the likelihood of displacement
did increase as time elapsed after positioning.
No relevant outcome studies have been published in the literature for any site including,
but not limited to, prostate, lung, and breast. Additionally, there are few registered
clinical trials of these techniques at this time, and none of a randomized design focused
on showing how these additional procedures may improve clinical outcomes, including a
decrease in toxicity to surrounding tissue.
Summary
Because real-time intra-fraction target tracking generally uses IMRT to deliver radiation
therapy, the use of real-time tracking is unlikely to produce outcomes that are inferior to
IMRT treatment. Thus, on this basis, the real-time tracking approach is not considered to
be investigational.
However, there are no data that indicate that use of real-time tracking during radiation
therapy to adjust the intra-fraction dose of radiation therapy or monitor target motion
during radiation treatment improves clinical outcomes over existing techniques. In
summary, because this technology is more costly than alternative services that produce
equivalent therapeutic results, this is considered not medically necessary.
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Practice Guidelines and Position Statements
The 2013 National Comprehensive Cancer Network (NCCN) clinical practice guidelines
for prostate cancer state “The accuracy of treatment should be improved by attention to
daily prostate localization, with techniques of IGRT [image-guided radiation therapy]
using CT[computed tomography], ultrasound implanted fiducials, electromagnetic
targeting/tracking, or an endorectal balloon to improve oncologic cure rates and reduce
side effects.” (12) NCCN has replaced 3D-CRT (conformal radiotherapy)/IMRT with
daily IGRT with IMRT/3D-CRT) throughout the guidelines. For primary EBRT; IGRT is
required if the dose is ≥78Gy. NCCN is applying a broader definition of IGRT and is
addressing inter-fraction (daily) adjustment rather than intra-fraction adjustments, which
are the focus of this policy. Although NCCN states that unless otherwise noted, all
recommendations are based on level 2A evidence, no specific citations are provided for
basis of their conclusions.
IMRT Head and Neck Cancers
This policy was originally created in 2009 and was regularly updated with searches of the
MEDLINE database. The most recent literature search was performed for the period of
July 2010 through April 2012. The following is a summary of the key findings to date.
Introduction
Intensity-modulated radiotherapy (IMRT) methods to plan and deliver radiation therapy
(RT) are not uniform. IMRT may use beams that remain on as multi-leaf collimators
(MLCs) that move around the patient (dynamic MLC) or that are off during movement
and turn on once the MLC reaches prespecified positions (“step and shoot” technique). A
third alternative uses a very narrow single beam that moves spirally around the patient
(tomotherapy). Each of these methods uses different computer algorithms to plan
treatment and yields somewhat different dose distributions in and outside the target.
Patient position can alter target shape and thus affect treatment plans. Treatment plans are
usually based on one imaging scan, a static 3-dimensional (3D) computed tomography
(CT) image. Current methods seek to reduce positional uncertainty for tumors and
adjacent normal tissues by various techniques. Patient immobilization cradles and skin or
bony markers are used to minimize day-to-day variability in patient positioning. In
addition, many tumors have irregular edges that preclude drawing tight margins on CT
scan slices when radiation oncologists contour the tumor volume. It is unknown whether
omitting some tumor cells or including some normal cells in the resulting target affects
outcomes of IMRT.
Head and Neck Cancers
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Systematic Reviews.
A systematic review published in 2008 summarized evidence on the use of IMRT for a
number of cancers, including head and neck, prostate, gynecologic, breast, lung, and
gastrointestinal tract. (1) This review mentions that the ability of IMRT to generate
concave dose distributions and tight dose gradients around targets may be especially
suitable to avoid organs at risk, such as the spinal cord or optic structures in head and
neck cancer.
This review identified 20 studies (1 randomized controlled trial [RCT] and 19 case series)
for IMRT in treatment of head and neck cancers. However, the RCT was for 2dimensional (2D) RT compared to IMRT. (2) Four studies (including the RCT) were for
treatment of nasopharyngeal carcinoma, 3 for sinonasal cancer, and 13 were for cancer
involving the oropharynx, hypopharynx, larynx, and oral cavity. The majority of the
studies reviewed showed a decrease in xerostomia with use of IMRT. However, there
was variability in measurement, e.g., flow rate versus symptoms. The case series of
sinonasal cancers showed less ocular toxicity (e.g., blindness) after use of IMRT. The
authors of this review recognize the limitations and biases of the studies used in their
analysis. With this limitation, they support the finding of decreased xerostomia (as well
as improved salivary gland function) with use of IMRT in head and neck cancers
involving the oral cavity, larynx, oropharynx, and hypopharyngeal area.
A comparative effectiveness review was published in 2010 on radiotherapy treatment for
head and neck cancers by Samson and colleagues from BCBSA’s Technology Evaluation
Center under contract with the Agency for Healthcare Research and Quality (AHRQ). (3)
This report noted that based on moderate evidence, IMRT reduces late xerostomia and
improves quality-of-life domains related to xerostomia compared with 3-dimensional
conformal radiation (3D-CRT). The report also noted that no conclusions on tumor
control or survival could be drawn from the evidence comparing IMRT to 3D-CRT.
In 2011, Tribius and Bergelt reviewed 14 studies that compared the quality-of-life
outcomes of head and neck cancer treatment with IMRT versus 2D-RT or 3D-CRT. (4)
The most commonly used quality of-life questionnaire was the European Organization
for Research and Treatment Quality-of-Life Questionnaire (EORTC QLQ-C30), which
was sometimes paired with the head and neck cancer module H&N35. Statistically
significant improvements were observed with IMRT over 2D-RT and 3-dimensional
conformal radiation (3D-CRT) in xerostomia, dry mouth, sticky saliva, and eating-related
functions. However, the authors noted the study populations were heterogeneous and
quality-of-life assessment tools varied. Therefore, further prospective randomized studies
were recommended. Other evidence reviews, in 2010, came to similar conclusions in that
treatment with IMRT resulted in reductions in acute and/or late xerostomia than other
radiotherapies for head and neck cancer. (5, 6)
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Randomized controlled trials.
An RCT by Pow and colleagues on IMRT for nasopharyngeal carcinoma was published
in 2006. (2) However, as noted above, this RCT compared IMRT to conventional, 2dimensional (2D) RT. In 2011, Nutting and colleagues reported on the PARSPORT
randomized Phase III trial, which also compared conventional RT to parotid-sparing
IMRT in 94 patients with T1-4, N0-3, M0 pharyngeal squamous-cell carcinoma. (7) One
year after treatment, grade 2 or worse xerostomia was reported in 38% of patients in the
IMRT group, which was significantly lower than the reported 74% in the conventional
RT group. Xerostomia continued to be significantly less prevalent 2 years after treatment
in the IMRT group (29% vs. 83%, respectively). At 24 months, rates of locoregional
control, non-xerostomia late toxicities, and overall survival were not significantly
different.
Non-randomized comparative studies.
In 2009, Vergeer et al. published a report that compared IMRT and 3D-CRT for patientrated acute and late xerostomia, and health-related quality of life (HRQoL) among
patients with head and neck squamous cell carcinoma (HNSCC). (8) The study included
241 patients with HNSCC (cancers arising from the oral cavity, oropharynx,
hypopharynx, nasopharynx, or larynx and those with neck node metastases from
squamous cell cancer of unknown primary) treated with bilateral irradiation with or
without chemotherapy. All patients were included in a program that prospectively
assessed acute and late morbidity and HRQoL at regular intervals. Before October 2004,
all patients were treated with 3D-CRT (n=150); starting in October 2004, 91 patients
received IMRT. The use of IMRT resulted in a significant reduction of the mean dose to
the parotid glands (27 Gy vs. 43 Gy; p<0.001). During radiation, grade 3 or higher
xerostomia at 6 weeks was significantly less with IMRT (approximately 20%) than with
3D-CRT (approximately 45%). At 6 months, the prevalence of grade 2 or higher
xerostomia was significantly lower after IMRT (32%) versus 3D-CRT (56%). Treatment
with IMRT also had a positive effect on several general and head and neck cancerspecific HRQoL dimensions. The authors concluded that IMRT results in a significant
reduction of xerostomia, as well as other head and neck symptoms, compared with
standard 3D-CRT in patients with HNSCC.
de Arruda and colleagues reported on their experience treating 50 patients with
oropharyngeal cancer (78% stage IV) with IMRT between 1998 and 2004. (9) Eighty-six
percent also received chemotherapy. This study found 2-year progression-free survival of
98% and regional progression-free survival of 88%, results similar to the 85% to 90%
rates for locoregional control reported in other published studies. The rate for grade 2
xerostomia was 60% for acute and 33% for chronic (after 9 months or more of followup); these rates are lower than the 60% to 75% generally reported with RT.
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Hoppe et al. reported on experience treating 37 patients with cancer of the paranasal
sinuses, nasal cavity, and lacrimal glands with postoperative IMRT between 2000 and
2007. (10) In this report with 28-month median follow-up, there was no early or late
grade 3 or 4 radiation–induced ophthalmologic toxicity. Two-year local progression-free
survival was 75%, and overall survival (OS) was 80%.
Braam et al. reported on a Phase II study that compared IMRT to conventional RT in
oropharyngeal cancer. (11) This study appeared to use 2D RT. The mean dose to the
parotid glands was 48 Gy for RT and 34 Gy for IMRT. Both stimulated parotid flow rate,
and parotid complications (more than 25% decrease in flow rate) were greater in the RT
group. At 6 months after treatment, 56% of IMRT patients and 81% of RT patients were
found to have parotid complications.
Rusthoven and colleagues compared outcomes with use of IMRT and 3D-CRT in patients
with oropharyngeal cancer. (12) In this study, in which 32 patients were treated with
IMRT and 23 with 3D-CRT, late xerostomia occurred in 15% of the IMRT patients and
94% of the 3D-CRT patients. There was also a trend toward improved locoregional
control of the tumor with IMRT.
Hodge and colleagues compared outcomes for patients with oropharyngeal cancer in the
pre-IMRT era to those obtained in the IMRT era. (13) In this study of 52 patients treated
by IMRT, the late xerostomia rate was 56% in the IMRT patients, compared to 63% in
those who did not receive IMRT. The authors noted that outcomes in these patients
improved at their institution since the introduction of IMRT but that multiple factors may
have contributed to this change. They also noted that even in the IMRT-era, the parotidsparing benefit of IMRT cannot always be used, for example, in patients with bulky
primary tumors and/or bilateral upper cervical disease.
Rades et al. reported on 148 patients with oropharyngeal cancer treated with RT. (14) In
this study, late xerostomia was noted in 17% of those treated with IMRT compared with
73% of those who received 3D-CRT and 63% of those who received standard radiation
therapy.
Thyroid Cancer
Studies on use of IMRT for thyroid cancers are few. In thyroid cancer, radiation therapy
is generally used for 2 indications. The first indication is treatment of anaplastic thyroid
cancer, and the second indication is potential use for locoregional control in patients with
incompletely resected high-risk or recurrent differentiated (papillary, follicular, or mixed
papillary-follicular) thyroid cancer. Anaplastic thyroid cancer occurs in a minority (less
than 5%) of thyroid cancer. The largest series comparing IMRT to 3D-CRT was
published by Bhatia and colleagues. (15) This study reviewed institutional outcomes for
anaplastic thyroid cancer treated with 3D-CRT or IMRT for 53 consecutive patients.
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Thirty-one (58%) patients were irradiated with curative intent. Median radiation dose was
55 gray (Gy; range, 4-70 Gy). Thirteen (25%) patients received IMRT to a median 60 Gy
(range, 39.9-69.0 Gy). The Kaplan-Meier estimate of overall survival (OS) at 1 year for
definitively irradiated patients was 29%. Patients without distant metastases receiving 50
Gy or higher had superior survival outcomes; in this series, use of IMRT versus 3D-CRT
did not influence toxicity. The authors concluded that outcomes for anaplastic thyroid
cancer treated with 3D-CRT or IMRT remain equivalent to historic results and that
healthy patients with localized disease who tolerate full-dose irradiation can potentially
enjoy prolonged survival. Schwartz and colleagues reviewed institutional outcomes for
patients treated for differentiated thyroid cancer with postoperative conformal externalbeam radiotherapy. (16) This was a single-institution retrospective review of 131
consecutive patients with differentiated thyroid cancer who underwent RT between
January 1996 and December 2005. Histologic diagnoses included 104 papillary, 21
follicular, and 6 mixed papillary-follicular types. Thirty-four patients (26%) had high-risk
histologic types and 76 (58%) had recurrent disease. Extraglandular disease spread was
seen in 126 patients (96%), microscopically positive surgical margins were seen in 62
patients (47%), and gross residual disease was seen in 15 patients (11%). Median RT
dose was 60 Gy (range, 38-72 Gy). Fifty-seven patients (44%) were treated with IMRT to
a median dose of 60 Gy (range, 56-66 Gy). Median follow-up was 38 months (range, 0134 months). Kaplan-Meier estimates of locoregional relapse-free survival, diseasespecific survival, and OS at 4 years were 79%, 76%, and 73%, respectively. On
multivariate analysis, high-risk histologic features, M1 (metastatic) disease, and gross
residual disease were predictors for inferior disease-specific and OS. IMRT did not
impact survival outcomes but was associated with less frequent severe late morbidity
(12% vs. 2%, respectively), primarily esophageal stricture. The authors concluded that
conformal external-beam radiotherapy provides durable locoregional disease control for
patients with high-risk differentiated thyroid cancer if disease is reduced to microscopic
burden and that IMRT may reduce chronic radiation morbidity, but additional study is
required.
Ongoing Clinical Trials
A search of online site Clinicaltrials.gov identified many studies on IMRT for head and
neck cancers. In a randomized Phase III trial, IMRT is being compared to conventional
radiation therapy for patients with oropharyngeal or hypopharyngeal cancer who are at
risk of developing xerostomia (NCT00081029). IMRT is being compared with 3D-CRT
in another randomized Phase III trial to determine hearing loss outcomes in patients who
have undergone parotid tumor surgery (NCT01216800). Several other studies will
evaluate IMRT with and without chemotherapy or monoclonal antibodies for head and
neck tumors. No clinical trials on IMRT for thyroid cancer were identified.
Clinical Input Received through Physician Specialty Societies and Academic
Medical Centers
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While the various physician specialty societies and academic medical centers may
collaborate with and make recommendations during this process through the provision of
appropriate reviewers, input received does not represent an endorsement or position
statement by the physician specialty societies or academic medical centers, unless
otherwise noted.
In response to requests, input was received from 2 physician specialty societies (3
reviewers) and 4 academic medical centers while this policy was under review in 2012.
There was uniform consensus in responses that suggested IMRT is appropriate for the
treatment of head and neck cancers. There was near-uniform consensus in responses that
suggested IMRT is appropriate in select patients with thyroid cancer. Respondents noted
IMRT for head, neck, and thyroid tumors may reduce the risk of exposure to radiation in
critical nearby structures such as the spinal cord and salivary glands, thus decreasing risks
of adverse effects such as xerostomia and esophageal stricture. Given the possible
adverse events that could result if nearby critical structures receive toxic radiation doses,
IMRT dosimetric improvements should be accepted as meaningful evidence for its
benefit.
Summary
Radiation therapy is an integral component in the treatment of head and neck cancers.
Intensity-modulated radiation therapy (IMRT) has been proposed as a method of
radiation therapy that allows adequate radiation therapy to the tumor while minimizing
the radiation dose to surrounding normal tissues and critical structures.
In general, the evidence to assess the role of IMRT in the treatment of cancers of the head
and neck suggests that IMRT provides tumor control rates comparable to existing
radiotherapy techniques. In addition, while results are not uniform across all studies, the
majority of the studies show a marked improvement in the rate of late xerostomia, a
clinically significant complication of radiation therapy that leads to decreased quality of
life for patients. Thus, based on the published literature that provides data on outcomes of
treatment, IMRT is a radiation therapy technique that can be used in the treatment of head
and neck cancers. Clinical input also provided uniform consensus that IMRT is
appropriate for the treatment of head and neck cancers. Therefore, its use in this clinical
application may be considered medically necessary.
There are limited data on use of IMRT for thyroid cancer. The published literature
consists of small case series with limited comparison among techniques for delivering
radiation therapy. Due to the limitations in this evidence, clinical input was obtained.
There was near-uniform consensus that the use of IMRT for thyroid tumors may be
appropriate in some circumstances such as for anaplastic thyroid carcinoma or for thyroid
tumors that are located near critical structures such as the salivary glands or spinal cord.
When possible adverse events could result if nearby critical structures receive toxic
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radiation doses, the ability to improve dosimetry with IMRT should be accepted as
meaningful evidence for its benefit. The results of the vetting, together with a strong
indirect chain of evidence and the potential to reduce harms, led to the decision that
IMRT may be considered medically necessary for the treatment of thyroid cancers in
close proximity to organs at risk (esophagus, salivary glands, and spinal cord) and 3dimensional conformal radiation (3-D CRT_ planning is not able to meet dose volume
constraints for normal tissue tolerance.
Practice Guidelines and Position Statements
The National Comprehensive Cancer Network (NCCN) guidelines on head and neck
cancers comment that, in order to minimize dose to critical structures, either IMRT or
3D-CRT is recommended for cancers of the oropharynx and nasopharynx, and maxillary
sinus or paranasal/ethmoid sinus tumors. The guidelines also indicate: “[t]he application
of IMRT to other sites (e.g., oral cavity, larynx, hypopharynx, salivary glands) is
evolving and may be used at the discretion of the treating physicians.” (17) NCCN
guidelines for thyroid cancer state that when considering external-beam radiation therapy
for the treatment of anaplastic thyroid cancer, IMRT may be useful to reduce toxicity.
(18)
The American College of Radiology and the American Society for Therapeutic Radiation
and Oncology note IMRT is a widely used treatment option for many indications
including head and neck tumors. (19)
The National Cancer Institute (NCI) indicates IMRT may be appropriate for head and
neck cancers in several instances. For radiation of cervical lymph nodes (for primary
cancer of unknown origin) and untreated primary occult metastatic squamous neck
cancer, IMRT may have less short- and long-term toxicity than conventional radiation
therapy in terms of xerostomia, acute dysphagia, and skin fibrosis. (20, 21) For
nasopharyngeal cancer, the NCI indicates IMRT results in a lower incidence of
xerostomia and may provide a better quality of life than conventional 3-D or 2-D
radiation therapy. (22) IMRT may also be appropriate in select cases of recurrent
nasopharyngeal cancer per the NCI. (22) Finally, to prevent or reduce the extent of
salivary gland hypofunction and xerostomia, the NCI indicates parotid-sparing IMRT is
recommended as a standard approach in head and neck cancers, if oncologically feasible.
(23)
IMRT of the Breast and Lung
General Information
Intensity -modulated radiation therapy (IMRT) methods to plan and deliver radiation
therapy are not uniform. (3-5) IMRT may use beams that remain “on” as multi-leaf
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collimator (MLC) devices move around the patient (dynamic MLC), or that are off during
movement and turn on once the MLC reaches prespecified positions (“step and shoot”
technique). A third alternative uses a very narrow single beam that moves spirally around
the patient (tomotherapy). Each of these methods uses different computer algorithms to
plan treatment and yields somewhat different dose distributions in and outside the target.
Patient position is another variable that can alter target shape and thus affect treatment
plans. Some investigators and clinicians deliver 3D-conformal radiation therapy (3DCRT) and IMRT with the patient prone, (6) while most treat supine patients as in
conventional (2D) external-beam radiation therapy (EBRT). A recent comparative
dosimetric analysis (published only as an abstract) concluded that target coverage is
similar with either position, but plans generated for the prone position spared more lung
tissue than those generated if the same patient was supine. (7) However, data are
unavailable to compare clinical outcomes for patients treated in prone versus supine
positions, and consensus is lacking.
Respiratory motion of the breast and internal organs (heart and lung) during radiation
treatments is another concern when using 3D-CRT or IMRT to treat breast cancer. (8, 9)
Treatment plans are usually based on one scan, a static 3-dimensional image. They
partially compensate for day-to-day (inter-fraction) variability in patient set-up, and for
(intra-fraction) motion of the target and organs at risk, by expanding the target volume
with uniform margins around the tumor (generally 0.5-1 cm for all positional
uncertainty).
Current methods and ongoing investigations seek to reduce positional uncertainty for
tumors and adjacent normal tissues by various techniques. Patient immobilization cradles
and skin or bony markers are used to minimize day-to-day variability in patient
positioning. Investigators are exploring an active breathing control device combined with
moderately deep inspiration breath-holding techniques to improve conformality and dose
distributions during IMRT for breast cancer. (8, 9) Techniques presently being studied
with other tumors (e.g., lung cancer ) (10) either gate beam delivery to the patient’s
respiratory movement or continuously monitor tumor (by in-room imaging) or marker
(internal or surface) positions to aim radiation more accurately at the target. The impact
of these techniques on outcomes of 3D-CRT or IMRT for breast cancer is unknown.
However, it appears likely that respiratory motion alters the dose distributions actually
delivered while treating patients from those predicted by plans based on static CT scans,
or measured by dosimetry using stationary (non-breathing) targets. In addition, non-small
cell lung cancer has more irregular, spiculated edges than many other tumors, including
breast cancer. This precludes drawing tight margins on computed tomography (CT) scan
slices when radiation oncologists contour the tumor volume. It is unknown whether
omitting some tumor cells or including some normal cells in the resulting target affects
outcomes of 3D-CRT or IMRT. Another, more recent concern for highly conformal
radiation therapy is the possibility that tumor size may change over the course of
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treatment as tumors respond or progress. Whether outcomes might be improved by
repeating scans and modifying treatment plans accordingly (termed adaptive radiation
therapy) is unknown.
These considerations emphasize the need to compare clinical outcomes rather than
treatment plan predictions to determine whether one radiotherapy method is superior to
another.
The literature search found no reports directly comparing health outcomes of IMRT with
those of 3D-CRT for either breast or lung cancer treatment. There were no prospective
comparative trials (randomized or nonrandomized). Since available data are scant, the
Report summarizes the studies that reported health outcomes.
Breast Cancer
Systematic reviews
In 2012, Dayes and colleagues published a systematic review that examined the evidence
for IMRT for whole-breast irradiation in the treatment of breast cancer to quantify its
potential benefits and to make recommendations for radiation treatment programs. (11)
Based on a review of 6 published reports through March 2009 (one randomized clinical
trial [RCT], 3 retrospective cohort studies, one historically controlled trial, and one
prospective cohort) including 2,012 patients, the authors recommended IMRT over
tangential radiotherapy after breast-conserving surgery to avoid acute adverse effects
associated with radiation. There were insufficient data to recommend IMRT over
standard tangential radiotherapy for reasons of oncological outcomes or late toxicity. The
RCT included in this review was the Canadian multi-center trial by Pignol and colleagues
reported below. In this RCT, IMRT was compared to 2D-RT, and CT scans were used in
treatment planning for both arms of the study; the types of tangential radiotherapy
regimens were not reported for the other studies. (2)
Two (of 6) cohort studies reviewed by Dayes and colleagues reported on breast cancerrelated outcomes. (11) Neither of these studies reported statistically significant
differences between treatment groups for contralateral breast cancer rates, clinical
recurrence-free survival or disease-specific survival. Despite differences in reported
outcomes, all 6 studies reported reductions in at least one measure of acute toxicity as a
result of IMRT-based breast radiation. These toxicities typically related to skin reactions
during the course of treatment, with reductions being in the order of one-third. The RCT
by Pignol and colleagues (reported below), for example, found a reduction in moist
desquamation specific to the inframammary fold by 39%. Only 2 retrospective cohort
studies reported on late toxicity effects; one cohort study reported a significant difference
between IMRT and tangential radiotherapy in favor of IMRT for breast edema (IMRT,
1% vs. 25%, p<0.001), and the other study found a trend toward a reduction in
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lymphedema rates (p=0.06). No differences were observed across both studies in other
late effects including fat necrosis or second malignancies. (11)
In 2010, Staffurth and colleagues conducted a review of clinical evidence from studies on
IMRT. (12) Included in the portion of the review addressing IMRT for breast cancer were
6 studies comparing the results of IMRT and 2D-radiation therapy (2D-RT) for
postoperative radiotherapy, including 2 randomized controlled trials (RCTs) [Donovan
and Pignol, noted below (1, 2)] and 4 nonrandomized comparative trials. The authors
reported that the studies showed improvements in long-term cosmesis and toxicity when
IMRT was used for breast cancer. However, health-related quality of life did not improve
with forward-planned IMRT when compared with conventional tangential breast 2D-RT.
Despite the lack of long-term health outcomes, the authors concluded reductions in
radiation-induced side effects were sufficient to warrant the use of IMRT.
Randomized and nonrandomized studies
Donovan et al. reported the treatment planning and dosimetry results from an ongoing
RCT comparing outcomes of radiation therapy for breast cancer using conventional 2DRT with wedged, tangential beams or IMRT (n=300) in 2002. (13) In an abstract, these
investigators reported interim cosmetic outcomes at 2 years after randomization for 233
evaluable patients. Changes in breast appearance were noted in 60 of 116 (52%)
randomly assigned to conventional external-beam radiation therapy (EBRT) and in 42 of
117 (36%) randomly assigned to IMRT (p=0.05). Other outcomes were not reported. In
2007, Donovan et al. published a subsequent report on this trial. (1) Enrolled patients had
‘higher than average risk of late radiotherapy-adverse effects’, which included patients
having larger breasts. The authors stated that while breast size is not particularly good at
identifying women with dose inhomogeneity falling outside current International
Commission on Radiation Units and Measurements guidelines, their trial excluded
women with small breasts (less than or equal to 500 cc), who generally have fairly good
dosimetry with standard 2D compensators. All patients were treated with 6 or 10 MV
photons to a dose of 50 Gy in 25 fractions to 100% in 5 weeks followed by an electron
boost to the tumor bed of 11.1 Gy in 5 fractions to 100%. The primary endpoint was
change in breast appearance scored from serial photographs taken before radiotherapy
and at 1, 2, and 5 years’ follow-up. Secondary endpoints included patient selfassessments of breast discomfort, breast hardness, quality of life, and physician
assessments of breast induration. Two-hundred forty (79%) patients with 5-year
photographs were available for analysis. Change in breast appearance was identified in
71/122 (58%) allocated standard 2D treatment compared to 47/118 (40%) patients
allocated 3D IMRT. Significantly fewer patients in the 3D IMRT group developed
palpable induration assessed clinically in the center of the breast, pectoral fold,
inframammary fold and at the boost site. No significant differences between treatment
groups were found in patient-reported breast discomfort, breast hardness, or quality of
life. The authors concluded that the analysis suggests that minimization of unwanted
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radiation dose inhomogeneity in the breast reduces late adverse effects. While the change
in breast appearance was statistically different, a beneficial effect on quality of life was
not demonstrated. Since whole-breast radiation therapy is now delivered by 3Dconformal techniques, these comparison data are of limited value. As the authors note,
quality-of-life changes were not noted. No other clinical outcomes were reported.
In a 2008 study, Donovan and colleagues evaluated methods for breast cancer IMRT
planning and compared IMRT methods to conventional wedge planning in 14 patients.
(14) The majority of IMRT plans were found to improve dose homogeneity over wedgeonly treatment plans. In patients with a breast size of 500 cm3 or greater, the dose
distribution improved between 5.6% and 11.1% (p<0.05), regardless of the planning
method used. The authors noted in the discussion that IMRT may be inappropriate for
patients with a breast volume of less than 1000 cm3.
In another RCT, IMRT was compared to 2D-RT, and computed tomography (CT) scans
were used in treatment planning for both arms of the study. Thus, this is close to the ideal
comparison of 3D-CRT and IMRT. In 2008, Pignol and colleagues reported on a
multicenter, double-blind, randomized clinical trial that was performed to determine if
breast IMRT would reduce the rate of acute skin reaction (moist desquamation), decrease
pain, and improve quality of life compared with radiotherapy using wedges. (2) Patients
were assessed each week during and up to 6 weeks after radiotherapy. A total of 358
patients were randomly assigned between July 2003 and March 2005 in 2 Canadian
centers, and 331 were included in the analysis. The authors noted that breast IMRT
significantly improved the dose distribution compared with 2D-RT. They also noted a
lower proportion of patients with moist desquamation during or up to 6 weeks after their
radiation treatment; 31% with IMRT compared with 48% with standard treatment
(p=0.002). A multivariate analysis found the use of breast IMRT and smaller breast size
were significantly associated with a decreased risk of moist desquamation. The use of
IMRT did not correlate with pain and quality of life, but the presence of moist
desquamation did significantly correlate with pain and a reduced quality of life. The
focus on short-term outcomes (6 weeks) is a limitation when assessing net health
outcome.
Barnett and colleagues have published baseline characteristics and dosimetry results of a
single-center randomized trial of IMRT for early breast cancer after breast-conserving
surgery. (15) In this trial, 1,145 patients with early breast cancer were evaluated for
EBRT. Twenty-nine percent had adequate dosimetry with standard radiotherapy. The
other 815 patients were randomly assigned to receive either IMRT or conventional 2DRT. In this study, inhomogeneity occurred most often when the dose-volume was greater
than 107% (V107) of the prescribed dose to greater than 2 cm3 breast volume with
conventional radiation techniques. When breast separation was greater than or equal to 21
cm, 90% of patients had received greater than V107 greater than 2 cm3 with standard
radiation planning. Subsequently, in 2012, Barnett and colleagues reported on the 2-year
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interim results of the trial. (16) The incidence of acute toxicity was not significantly
different between groups. Additionally, photographic assessment scores for breast
shrinkage were not significantly different between groups. The authors noted overall
cosmesis after RT or IMRT was dependent upon surgical cosmesis, suggesting breast
shrinkage and induration were due to surgery rather than RT, thereby masking the
potential cosmetic benefits of IMRT.
Several other publications report findings from single institutions from patients who
received IMRT compared to patients who received 2D-RT (nonrandomized studies). The
grading of acute radiation dermatitis is relevant to these studies. Acute radiation
dermatitis is graded on a scale of 0 to 5, with 0 as no change and 5 as death. Grade 2 is
moderate erythema and patchy moist desquamation, mostly in skin folds; grade 3 is moist
desquamation in other locations and bleeding with minor trauma.
McDonald et al. reported on a single institution retrospective review of patients who
received radiation therapy after conservative surgery for Stages 0-III breast cancer from
January 1999 to December 2003. (17) Computed tomography simulation was used to
design standard tangential breast fields with enhanced dynamic wedges for 2D-RT and
both enhanced dynamic wedges and dynamic multileaf collimators for IMRT. In this
report, 121 breasts were treated with IMRT and 124 with 2D-RT. Median breast dose was
50 Gy in both groups. Median follow-ups were 6.3 years (range: 3.7–104 months) for
patients treated with IMRT and 7.5 years (range: 4.9–112 months) for those treated with
2D-RT. Decreased acute skin toxicity of Radiation Therapy Oncology Group (RTOG)
grade II or III was observed with IMRT treatment compared with 2D-RT (39% vs. 52%,
respectively; p=0.047). For patients with Stages I-III (n=199), 7-year Kaplan-Meier
freedom from ipsilateral breast tumor recurrence (IBTR) rates were 95% for IMRT and
90% for 2D-RT (p=0.36). For patients with stage 0 (ductal carcinoma in situ, n=46), 7year freedom from IBTR rates were 92% for IMRT and 81% for 2D-RT (p=0.29). There
were no statistically significant differences in overall survival (OS), disease-specific
survival, or freedom from IBTR, contralateral breast tumor recurrence, distant metastasis,
late toxicity, or second malignancies between IMRT and 2D-RT. The authors concluded
that patients treated with breast IMRT had decreased acute skin toxicity, and long-term
follow-up showed excellent local control. Interpretation of this study is limited by its
retrospective design and limited outcome measures (no quality of life measures).
Kestin et al. reported they had treated 32 patients with early-stage breast cancer using
multiple static multileaf collimator (MLC) segments to deliver IMRT for whole-breast
irradiation. (18) With at least 1 month of follow-up on all patients, they observed no
grade III or greater acute skin toxicity (using RTOG criteria). However, follow-up was
inadequate to assess other health outcomes.
A subsequent report from Vicini and colleagues included 281 patients with early breast
cancer treated with the same IMRT technique. (19) Of these, 102 (43%) experienced
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RTOG grade II, and 3 (1%) experienced grade III skin toxicity. Cosmetic results at 1 year
after treatment were reported for 95 patients and were good to excellent in 94 (99%). No
patients had skin telangiectasias, significant fibrosis, or persistent breast pain. Other
primary or secondary outcomes were not reported.
Many reports in the literature described changes in radiation dose delivered for IMRT
compared to other techniques. For example, Selvaraj reported on 20 patients with breast
cancer randomly selected for comparison who received IMRT or 3D-CRT. (20) In this
study, the mean dose for the ipsilateral lung and the percentage of volume of contralateral
volume lung receiving greater than 5% of prescribed dose with IMRT were reduced by
9.9% and 35% compared to 3D CRT. The authors note that the dosimetric data suggest
improved dose homogeneity in the breast and reduction in the dose to lung and heart for
IMRT treatments, which may be of clinical value in potentially contributing to improved
cosmetic results and reduced late treatment-related toxicity.
Hardee and colleagues compared the dosimetric and toxicity outcomes after treatment
with IMRT or 3D-CRT for whole-breast irradiation in a consecutive series of 97 patients
with early-stage breast cancer, who were assigned to either approach after segmental
mastectomy based upon insurance carrier approval for reimbursement for IMRT. (21)
IMRT significantly reduced the maximum dose to the breast (Dmax median, 110% for
3D-CRT vs. 107% for IMRT; p<0.0001, Wilcoxon test) and improved median dose
homogeneity (median, 1.15 for 3D-CRT vs. 1.05 for IMRT; p<0.0001, Wilcoxon test)
when compared with 3D-CRT. These dosimetric improvements were seen across all
breast volume groups. Grade 2 dermatitis occurred in 13% of patients in the 3D-CRT
group and 2% in the IMRT group. IMRT moderately decreased rates of acute pruritus
(p=0.03, chi-square test) and grade 2 to 3 sub-acute hyperpigmentation (p=0.01, Fisher
exact test). With a minimum of 6 months’ follow-up, the treatment was reported to be
similarly well-tolerated in either group, including among women with large breast
volumes. (21)
Freedman and colleagues studied the time spent with radiation-induced dermatitis during
a course of radiation therapy for women with breast cancer treated with conventional
radiation therapy (2D-RT) or IMRT. (22) For this study, the population consisted of 804
consecutive women with early-stage breast cancer treated with breast-conserving surgery
and radiation from 2001 to 2006 at the Fox Chase Cancer Center. All patients were
treated with whole-breast radiation followed by a boost to the tumor bed. Whole-breast
radiation consisted of conventional wedged photon tangents (n=405) earlier in the study
period, and mostly of photon IMRT (n=399) in later years. All patients had acute
dermatitis graded each week of treatment. The breakdown of cases of maximum toxicity
by technique was as follows: 48%, grade 0/1, and 52%, grade 2/3, for IMRT; and 25%,
grade 0/1, and 75%, grade 2/3, for conventional radiation therapy (p<0.0001). The IMRT
patients spent 82% of weeks during treatment with grade 0/1 dermatitis and 18% with
grade 2/3 dermatitis, compared with 29% and 71% of patients, respectively, treated with
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conventional radiation (p<0.0001). From this pre/post study, the authors concluded that
breast IMRT is associated with a significant decrease both in the time spent during
treatment with grade 2/3 dermatitis and in the maximum severity of dermatitis compared
with that associated with conventional radiation. Interpretation of these results is limited
by lack of a contemporaneous comparison. The investigators have subsequently reported
on 5-year outcomes of the Fox Chase Cancer Center experience using whole-breast
IMRT for the treatment of early-stage breast cancer; the 5-year actuarial ipsilateral breast
tumor recurrence and locoregional recurrence rates were 2.0% and 2.4%, respectively. In
terms of treatment-related effects, edema and erythema were consistently noted early
after breast IMRT and peaked at 3-6 months from the start of whole-breast IMRT.
Infection was rare, with <1.5% of the patient population experiencing this side effect;
telangectasia was noted to develop in approximately 8% of patients, and fibrosis in 7% of
patients, at ≥36 months from the start of whole-breast IMRT. (23) Publications also
report on the potential ability of IMRT to reduce radiation to the heart (left ventricle) in
patients with left-sided breast cancer and unfavorable cardiac anatomy. (24) This is a
concern because of the potential development of late cardiac complications, such as
coronary artery disease, following radiation therapy to the left breast.
IMRT has also been investigated as a technique of partial-breast irradiation, as an
alternative to whole-breast irradiation therapy after breast-conserving surgery. Breast
brachytherapy (see policy No. 8.01.13) is another technique of partial-breast irradiation
therapy. Leonard et al. reported on 55 patients treated with partial-breast IMRT who had
mean follow-up of 10 months. (25) At the short-term follow-up, the dose delivery and
clinical outcomes were considered acceptable; however, long-term follow-up is needed.
In 2010, Livi et al. reported on preliminary results of 259 patients randomized in a Phase
III trial, that began in September 2008, to compare conventional fractionated wholebreast treatment (n=128) to accelerated partial-breast irradiation plus IMRT (n=131). (26)
RTOG grade 1 and 2 skin toxicity was observed at a rate of 22% and 19% in the whole
breast treatment group versus 5% and 0.8% in the partial breast treatment group,
respectively. The authors concluded partial-breast irradiation with IMRT is feasible but
noted long-term results on health outcomes are still needed. Additionally, 18 months after
radiation therapy (RT), 1 case of contralateral breast cancer was diagnosed in the
partial0breast irradiation group, creating concern from the authors that it may be related
to the high dosage of IMRT.
Few studies have examined the use of IMRT for chest wall irradiation in postmastectomy
breast cancer patients and no studies were identified that reported on health outcomes for
this indication. Available studies have focused on treatment planning and techniques to
improve dose distributions to targeted tissues while reducing radiation to normal tissue
and critical surrounding structures, such as the heart and lung. An example of one
available study was published by Rudat and colleagues, in which treatment planning for
chest wall irradiation with IMRT was compared to 3D-CRT in 20 postmastectomy
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patients. (27) The authors reported IMRT resulted in significantly decreased heart and
lung high-dose-volume with a significantly improved conformity index when compared
to 3D-CRT. However, there was no significant difference reported in the homogeneity
index. The authors noted longer-term prospective studies are needed to further assess
cardiac toxicity and secondary lung cancer risk with multi-field IMRT, which while
reducing high dose-volume, increases mean heart and lung dose. As noted, health
outcomes were not reported in this study.
Lung Cancer
Systematic reviews
In 2012, Bezjak and colleagues published a systematic review that examined the evidence
for the use of IMRT in the treatment of lung cancer in order to quantify its potential
benefits and make recommendations for radiation treatment programs considering
adopting this technique within Ontario, Canada. (28) This review consisted of 2
retrospective cohort studies (through March 2010) reporting on cancer outcomes, which
was considered insufficient evidence on which to make evidence-based
recommendations. These 2 cohort studies reported on data from the same institution
(M.D. Anderson Cancer Center); the study by Liao and colleagues (2010, reported
below) (29) acknowledged that patients included in their cohort (n=409) were previously
reported on in the earlier cohort by Yom and colleagues (n=290), but it is not clear
exactly how many patients were added in the second report. However, due to the known
dosimetric properties of IMRT and extrapolating from clinical outcomes from other
disease sites, the review authors recommended that IMRT should be considered for lung
cancer patients where the tumor is in close proximity to an organ at risk, where the target
volume includes a large volume of an organ at risk, or in scenarios where dose escalation
would be potentially beneficial while minimizing normal tissue toxicity. (28)
Randomized and nonrandomized studies
Holloway et al. reported on a Phase I dose escalation study of IMRT for patients with
lung cancer that was terminated after the first 5 patients received 84 Gy in 35 fractions
(2.4 Gy per fraction). (30) Treatment planning used combined CT and positron emission
tomography for volumetric imaging, and treatment beams were gated to patients’
respiration. Acute toxicities included 1 patient with RTOG grade II dysphasia, 1 with
grade I odynophagia, and 1 with grade I skin desquamation. In addition, 1 patient died of
lung toxicity and was shown on autopsy to have bilateral diffuse pulmonary fibrosis with
emphysema and diffuse alveolar damage. Of those who survived, 1 remained disease-free
at 34 months, 2 developed metastases, and 1 developed an in-field recurrence.
Noting that the use of IMRT for inoperable non-small cell lung cancer (NSCLC) had not
been well-studied, Sura and colleagues reviewed their experience with IMRT for patients
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with inoperable NSCLC. (31) They reported a retrospective review of 55 patients with
Stage I-IIIB inoperable NSCLC treated with IMRT between 2001 and 2005. The study
endpoints were toxicity, local control, and overall survival. With a median follow-up of
26 months, the 2-year local control and overall survival rates for Stage I/II patients were
50% and 55%, respectively. For the Stage III patients, 2-year local control and overall
survival rates were 58% and 58%, respectively, with a median survival time of 25
months. Six patients (11%) experienced grade 3 acute pulmonary toxicity; 2 patients
(4%) had grade 3 or worse late treatment-related pulmonary toxicity. The authors
concluded that these results were promising
Liao and colleagues report on a nonrandomized comparative study of patients who
received one of these forms of radiation therapy, along with chemotherapy, for inoperable
NSCLC at one institution (M.D. Anderson Cancer Center). (29) This study involved a
retrospective comparison of 318 patients who received CT/3D-CRT and chemotherapy
from 1999–2004 (mean follow-up of 2.1 years) to 91 patients who received 4dimensional computed tomography (4DCT)/IMRT and chemotherapy from 2004–2006
(mean follow-up of 1.3 years). Both groups received a median dose of 63 Gy. Disease
endpoints were locoregional progression, distant metastasis, and overall survival (OS).
Disease covariates were gross tumor volume (GTV), nodal status, and histology. The
toxicity endpoint was grade III or greater radiation pneumonitis; toxicity covariates were
GTV, smoking status, and dosimetric factors. Data were analyzed using Cox proportional
hazards models. The hazard ratios for IMRT were less than 1 for all disease endpoints;
the difference was significant only for OS. The median survival was 1.40 (standard
deviation [SD]: 1.36) years for the IMRT group and 0.85 (SD: 0.53 years) for the 3DCRT group. The toxicity rate was significantly lower in the IMRT group than in the 3DCRT group. The V20 (volume of the lung receiving 20 Gy) was higher in the 3D-CRT
group and was a factor in determining toxicity. Freedom from distant metastasis was
nearly identical in both groups. The authors concluded that treatment with 4DCT/IMRT
was at least as good as that with 3D-CRT in terms of the rates of freedom from
local/regional progression and metastasis. This retrospective study found a significant
reduction in toxicity and improvement in survival. The nonrandomized, retrospective
aspects of this study from one center limit the ability to draw definitive conclusions from
this report.
In a 2012 follow-up study, Liao and colleagues (Jiang et al.) published long-term followup data from the M.D. Anderson Cancer Center on the use of definitive IMRT, with or
without chemotherapy, for newly diagnosed, pathologically confirmed, inoperable
NSCLC from 2005 to 2006. (32) This retrospective review included 165 patients, 89% of
whom had Stage III to IV disease. The median radiation dose was 66 Gy given in 33
fractions. Median overall survival time was 1.8 years; the 2-year and 3-year overall
survival rates were 46% and 30%, respectively. Rates of grade ≥3 maximum treatmentrelated pneumonitis were 11% at 6 months and 14% at 12 months. At 18 months, 86% of
patients had developed grade ≥1 maximum pulmonary fibrosis, and 7% grade ≥2 fibrosis.
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The median times to maximum esophagitis were 3 weeks (range, 1-13 weeks) for grade 2
and 6 weeks (range, 3-13 weeks) for grade 3. These rates of treatment-related toxicities
with IMRT have been reported in other series to be no different than that in patients
treated with 3D-CRT. (33, 34)
Ongoing Clinical Trials
A search of the online site Clinicaltrials.gov identified at least 3 randomized Phase III
studies comparing IMRT to 3D-CRT for breast cancer after breast-conserving surgery.
One study addresses partial-breast radiotherapy (NCT01185132), and 2 studies address
whole-breast radiotherapy (NCT01322854 and NCT01349322). In addition, a follow-up
study of the Canadian RCT by Pignol and colleagues (2008) is being undertaken to assess
the long-term outcomes of breast irradiation using IMRT (NCT01803139). In this study
the investigators will recall all patients (n=358) enrolled in the original trial at 8 years to
assess whether this technique also reduces permanent side effects including pain and
cosmesis. This study will be open for recruitment in April 2013, with the estimated
completion date of June 2014.
A randomized intergroup trial that compared whole-breast and accelerated partial-breast
irradiation, including IMRT, sponsored by the U.S. National Cancer Institute and led by
the National Surgical Adjuvant Breast and Bowel Project and the RTOG opened in early
2005 (NCT00103181). The trial is randomly assigning 4,300 patients (2,150 per
treatment arm) to whole-breast or partial-breast irradiation after lumpectomy with tumorfree margins verified by histologic examination. The primary objective is to compare inbreast tumor control (i.e., recurrence rates) for whole-breast versus partial-breast
irradiation. Investigators anticipate accrual will be completed within 4.6 years (June
2015) from the trial‘s start date. Lacking data with adequate follow-up from this or
similar RCTs, there is inadequate published evidence to permit scientific conclusions
about partial -breast irradiation, regardless of whether it is delivered by IMRT or breast
brachytherapy.
One randomized Phase III trial for limited-stage small cell lung cancer treatment was
identified comparing 3 different chest radiation therapy regimens, including IMRT,
(NCT00632853). This U.S. multicenter trial has an estimated enrollment of 729 patients
and is sponsored by the Cancer and Leukemia Group B, in collaboration with the
Radiation Therapy Oncology Group and the National Cancer Institute. The primary
outcome measure is overall survival time between 3 treatment arms. This study is
currently recruiting participants with the estimated completion date of June 2023. In
addition, a Phase III study from the M.D. Anderson Cancer Center is comparing 3D-CRT
versus IMRT using 4-Dimensional CT Planning and image guided adaptive radiation
therapy in 168 patients with locally-advanced NSCLC receiving concurrent chemoradiation. The primary outcome measure is time to grade 3 pneumonitis. This study has
closed but the results have not been published (NCT00520702).
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Clinical Input Received through Physician Specialty Societies and Academic
Medical Centers
While the various physician specialty societies and academic medical centers may
collaborate with and make recommendations during this process through the provision of
appropriate reviewers, input received does not represent an endorsement or position
statement by the physician specialty societies or academic medical centers, unless
otherwise noted.
2010
In response to requests, input was received from 1 physician specialty society and 2
academic medical centers (3 reviewers) while this policy was under review in 2010.
Those providing input suggested that IMRT should be utilized in select patients with
breast cancer (e.g., some cancers involving the left breast) and lung cancer (e.g., some
large cancers).
2012
In response to requests, input was received from 2 physician specialty societies and 3
academic medical centers (3 reviewers) while this policy was under review in 2011.
There was near uniform consensus in responses that suggested whole-breast and lung
IMRT are appropriate in select patients with breast and lung cancer. Respondents noted
IMRT may reduce the risk of cardiac, pulmonary, or spinal cord exposure to radiation in
some cancers such as those involving the left breast or large cancers of the lung.
Respondents also indicated whole-breast IMRT may reduce skin reactions and potentially
improve cosmetic outcomes. Partial breast IMRT was not supported by the respondents,
and the response was mixed on the value of chest wall IMRT postmastectomy.
Summary
For the treatment of breast cancer, based on randomized and nonrandomized comparative
studies, whole-breast intensity-modulated radiation therapy (IMRT) appears to produce
clinical outcomes comparable to that of 3D-conformal radiation therapy (CRT). In
addition, there is some evidence for decrease in acute skin toxicity with IMRT compared
to 2D radiotherapy. Dosimetry studies have demonstrated that IMRT reduces
inhomogeneity of radiation dose, thus potentially providing a mechanism for reduced
skin toxicity. One RCT reported improvements in moist desquamation of skin, but did
not report differences in grade 3-4 skin toxicity, pain symptoms, or quality of life.
Another RCT reported no differences in cosmetic outcome at 2 years for IMRT compared
with 2D radiotherapy. There was strong support through clinical vetting for the use of
IMRT in breast cancer for left-sided breast lesions in which alternative types of
radiotherapy cannot avoid toxicity to the heart. Based on the available evidence and
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results of input from clinical vetting, in conjunction with a strong indirect chain of
evidence and the potential to reduce harms, IMRT may be considered medically
necessary for whole-breast irradiation when 1) alternate forms of radiotherapy cannot
avoid cardiac toxicity, and 2) IMRT dose planning demonstrates a substantial reduction
in cardiac toxicity.
Studies on IMRT for partial-breast irradiation are limited and have not demonstrated
improvements in health outcomes. Therefore, partial-breast IMRT in the treatment of
breast cancer is considered investigational.
No studies have reported on health outcomes after IMRT for chest wall irradiation in
postmastectomy breast cancer patients. Available studies have only focused on treatment
planning and techniques. The risk of secondary lung cancers and cardiac toxicity needs to
be further evaluated. Therefore, IMRT for chest wall irradiation in postmastectomy breast
cancer patients is considered investigational.
For the treatment of lung cancer, based on nonrandomized comparative studies, IMRT
appears to produce clinical outcomes comparable to that of 3D-conformal radiation
therapy. Dosimetry studies report that IMRT can reduce radiation exposure to critical
surrounding structures, especially in large lung cancers. Results of clinical vetting
indicate strong support for IMRT when alternative radiotherapy dosimetry exceeds a
threshold of 20 Gy dose-volume (V20) to at least 35% of normal lung tissue. As a result
of available evidence and clinical vetting, in conjunction with a strong indirect chain of
evidence and potential to reduce harms, IMRT of the lung may be considered medically
necessary for lung cancer when: 1) radiotherapy is given with curative intent, 2) alternate
radiotherapy dosimetry demonstrates radiation dose exceeding 20 Gy dose-volume (V20)
for at least 35% of normal lung tissue, and 3) IMRT reduces the 20-Gy dose-volume
(V20) of radiation to the lung at least 10% below the V20 of 3-D conformal radiation
therapy (e.g., 40% reduced to 30%). IMRT for the palliative treatment of lung cancer is
considered not medically necessary since conventional radiation techniques are adequate
for palliation.
Practice Guidelines and Position Statements
The current National Comprehensive Cancer Network (NCCN) guidelines for breast
cancer indicate that for whole-breast irradiation, uniform dose distribution and
minimization of toxicity to normal tissue are the objectives and list various approaches to
achieve this, including IMRT. (35) The guidelines note accelerated partial-breast
irradiation is generally considered investigational and should be limited to use in clinical
trials. Additionally, IMRT is not mentioned as a technique in partial-breast irradiation.
The guidelines indicate chest wall and regional lymph node irradiation may be
appropriate post-mastectomy in select patients, but IMRT is not mentioned as a technique
for irradiation in these circumstances.
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The current NCCN guidelines for non-small cell lung cancer indicate that “more
advanced technologies are appropriate when needed to deliver curative radiation therapy
safely. These technologies include (but are not limited to) IMRT...Nonrandomized
comparisons of using advanced technologies versus older techniques demonstrate
reduced toxicity and improved survival.” (36)
The current NCCN guidelines for small cell lung cancer indicate 3D-CRT techniques are
preferred and IMRT may be considered in select patients. (37)
The American Society for Radiation Oncology published consensus guidance on
radiation to the lung in 2010. The guidance recommends limiting the 20-Gy dose-volume
(V20) of radiation to the lung to less than or equal to 30–35% and mean lung dose to less
than or equal to 20-23 Gy (with conventional fractionation) to reduce the risk of radiation
pneumonitis to less than or equal to 20%
IMRT of Abdomen and Pelvis
Introduction
Methods to plan and deliver intensity-modulated radiation therapy (IMRT) methods are
not uniform.(1-3) IMRT may use beams that remain on as the multileaf collimator (MLC)
moves around the patient (dynamic MLC), or that are turned off during movement and
turned on when the MLC reaches prespecified positions (“step and shoot” technique). A
third alternative uses a very narrow single beam that moves spirally around the patient
(tomotherapy). Each of these methods uses different computer algorithms to plan
treatment and yields somewhat different dose distributions in and outside the target.
Patient position can alter target shape and thus affect treatment plans. IMRT may be
delivered with the patient in the prone or supine position. However, data are unavailable
to compare clinical outcomes for patients treated in prone versus supine positions, and
consensus is lacking. Respiratory motion of the internal organs during radiation
treatments is another concern when using IMRT to treat lesions in those compartments.
Treatment plans are usually based on one imaging scan, a static 3-dimensional computed
tomography (CT) image. They partially compensate for day-to-day (inter-fraction)
variability in patient set-up, and for (intrafraction) motion of the target and organs at risk,
by expanding the target volume with uniform margins around the tumor (generally 0.5–1
cm for all positional uncertainty).
Current methods seek to reduce positional uncertainty for tumors and adjacent normal
tissues by various techniques. Patient immobilization cradles and skin or bony markers
are used to minimize day-to-day variability in patient positioning. An active breathing
control device combined with moderately deep inspiration breath-holding techniques may
be used to improve conformality and dose distributions during IMRT. Other techniques
being studied with internal tumors include gate beam delivery to the patient’s respiratory
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movement or continuous monitor of tumor (by in-room imaging) or marker (internal or
surface) positions to aim radiation more accurately at the target. The impact of these
techniques on outcomes of IMRT for any cancer is unknown. However, it appears likely
that respiratory motion alters the dose distributions actually delivered while treating
patients from those predicted by plans based on static CT scans, or measured by
dosimetry, using stationary (non-breathing) targets. In addition, many tumors have
irregular edges that preclude drawing tight margins on CT scan slices when radiation
oncologists contour the tumor volume. It is unknown whether omitting some tumor cells
or including some normal cells in the resulting target affects outcomes of IMRT. Finally,
tumor size may change over the course of treatment as tumors respond or progress, which
has potential effects on radiation dose delivery and distribution. Whether outcomes might
be improved by repeating scans and modifying treatment plans accordingly (termed
adaptive radiation therapy) is unknown.
The Advanced Technology Consortium (ATC) has helped to develop general guidelines
for protocols that incorporate IMRT as an option. These guidelines were communicated
to all clinical trial groups by the National Cancer Institute (NCI) and clearly stated that
respiratory motion could cause far more problems for IMRT than for traditional
radiotherapy treatments (ATC Guidelines for use of IMRT for intra-thoracic
treatments).
These considerations emphasize the need to compare clinical outcomes rather than
treatment plan predictions to determine whether one radiotherapy method is superior to
another.
Technology Assessments and Systematic Reviews
Two reviews summarized evidence on the use of IMRT for a number of cancers,
including head and neck, prostate, gynecologic, breast, lung, and gastrointestinal.(4,5)
The authors presented the reviews as analysis of comparative clinical studies; in reality,
they categorized several small case series using historical cohorts as controls as
comparative studies for several tumor types. This method limits the value of the reviews
in assessing the role of IMRT for the diseases addressed in this policy.
Primary Literature
Literature searches have identified no studies that directly compare health outcomes with
IMRT versus those in patients treated concurrently with any other type of radiotherapy
for tumors of the thorax (e.g., esophagus), upper abdomen (e.g., stomach, pancreas, bile
duct, liver), or pelvis (e.g., rectal, anal, gynecologic). Case series and single-arm studies
of IMRT have been identified, including some with historical controls treated with nonIMRT methods.
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Gastrointestinal Tract
Stomach
As outlined in a recent review article, IMRT has been investigated for treatment of
gastric cancer in several studies, but only one reported clinical outcomes.(1) In a small
(n=7) case series, patients with stage III gastric cancer received postoperative
chemoradiotherapy with 5-fluorouracil (5FU) and leucovorin and IMRT delivered to a
dose of 50.4 Gy in 1.8 Gy fractions.(6) Chemoradiotherapy with IMRT was welltolerated, with no acute gastrointestinal (GI) tract toxicities (nausea, diarrhea,
esophagitis) greater than grade 2.
The efficacy and safety of 2 different adjuvant chemoradiotherapy regimens using 3dimensional conformal radiation (3D-CRT) (n=27) or IMRT (n=33) were evaluated in 2
consecutive cohorts of patients who underwent primarily D2 resection for gastric
cancer.(7) The cohorts in this study were generally well-matched, with American Joint
Committee on Cancer (AJCC) advanced stage (II-IV) disease. The majority (n=26, 96%)
of those who received 3D-CRT were treated with 5-fluorouracil plus folinic acid
(5FU/FA); the other patient received oxaliplatin plus capecitabine (XELOX). In the 3DCRT cohort, 13 (50%) patients completed the 5FU/FA regimen, 13 halted early because
of acute toxicity or progression and received a median 60% of planned cycles. Patients in
the IMRT cohort received XELOX (n=23, 70%) or 5FU/FA (n=10, 30%). Five of 10
(50%) patients completed all planned 5FU/FA cycles, the other 5 received only a median
60% of cycles because of acute toxicity. Thirteen (56%) treated with XELOX completed
all planned cycles; the other 10 received a median of 70% planned cycles because of
toxicity. Radiation was delivered to a total prescribed dose of 45 Gy/1.8 Gy/fraction in 21
(81%) of the 3D-CRT cohort patients; 5 received less than 45 Gy because of intolerance
to treatment. Thirty (91%) patients in the IMRT cohort received the planned 45 Gy
dosage; 2 (6%) were unable to tolerate the full course, and 1 case planned for 50.4 Gy
was halted at 47 Gy. The median overall survival (OS) was 18 months in the 3D-CRT
cohort, and more than 70 months in the IMRT cohort (p=0.0492). The actuarial 2-year
OS rates were 67% in the IMRT cohort and 37% in the 3D-CRT group (p not reported).
Acute renal toxicity based on creatinine levels was generally lower in the IMRT cohort
compared to the 3D-CRT group, with a significant difference observed at 6 weeks
(p=0.0210). In the 3D-CRT group, LENT-SOMA grade 2 renal toxicity was observed in
2 patients (8%) whereas no grade 2 toxicity was reported in the IMRT group.
Hepatobiliary
In a retrospective series with a historical control cohort, clinical results achieved with
image-guided IMRT (n=24) were compared to results with CRT (n=24) in patients with
primary adenocarcinoma of the biliary tract.(8) The majority of patients underwent
postsurgical chemoradiotherapy with concurrent fluoropyrimidine-based regimens. IMRT
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treatment plans prescribed 46 to 56 Gy to the planning target volume (PTV) that includes
the tumor and involved lymph nodes, in daily fractions of 1.8–2 Gy. CRT involved 3-D
planning that delivered 46–50 Gy in 1.8–2 Gy daily fractions. Both groups received boost
doses of 4–18 Gy as needed. The median estimated overall survival (OS) for all patients
who completed treatment was 13.9 months (range: 9.0–17.6); the IMRT cohort had
median OS of 17.6 months (range: 10.3–32.3), while the CRT cohort had a median OS of
9.0 months (range: 6.6–17.3). Acute GI toxicities were mild to moderate, with no
significant differences between patient cohorts. These results suggest that moderate dose
escalation via conformal radiotherapy is technically and clinically feasible for treatment
of biliary tract adenocarcinoma. However, while this series represents the largest group of
patients with this disease treated with IMRT, generalization of its results is limited by the
small numbers of patients, use of retrospective chart-review data, nonrepresentative case
spectrum (mostly advanced/metastatic disease), and comparison to a nonconcurrent
control radiotherapy cohort.
Two single arm studies reported outcomes with IMRT in patients with hepatobiliary
cancers. The first study involved 42 patients with advanced (33% AJCC stage IIIC, 67%
stage IV) hepatocellular carcinoma (HCC) with multiple extrahepatic metastases.(9)
Among the 42 cases, 33 (79%) had intrahepatic HCC with extrahepatic metastases, 9
(21%) had only extrahepatic lesions. The extrahepatic locations of HCC metastatic
lesions included lung (n=19), lymph node and adrenal (n=20), other soft tissues (n=6),
and bone (n=5). Helical tomotherapy was performed simultaneously for all lesions in
each patient, with a total radiation dose of 50 and 40 Gy to 95% of the gross tumor
volume (GTV) and PTV in 10 fractions divided over 2 weeks. All received capecitabine
during the course of IMRT as a radiosensitizer. After completion of tomotherapy,
additional transarterial or systemic chemotherapy was administered to patients eligible
for it according to tumor location. Among 31 patients who underwent hepatic IMRT, a
mean of 3 courses (range: 1-6) transarterial chemolipiodolization was performed in 23.
Among 9 patients with extrahepatic lesions only, 3 received an additional 3-7 cycles of
systemic chemotherapy consisting of epirubicin, cisplatin, and 5FU. Median follow-up
was 9.4 months (range: 1.9–25.3 months). Tumor response was reported separately for
each organ treated with IMRT. The overall objective tumor response rate was 45% for
intrahepatic HCC, 68% for pulmonary lesions, 60% for lymph node and adrenal cases,
and 67% for soft tissue metastases. Three cases of local tumor progression occurred
within the target radiation area, including 2 intrahepatic HCC and 1 abdominal lymph
node metastasis. Median OS was 12.3 months, with 15% OS at 24 months. The most
common acute adverse events were mild anorexia and constitutional symptoms that
occurred 1-2 weeks after start of IMRT, regressed spontaneously or subsided with
symptomatic care, and did not interfere with the scheduled delivery of IMRT. However,
it is not possible to discern the impact of IMRT on adverse events because almost all
occurred in patients who received chemotherapy following IMRT. However, most
patients were reported to have tolerated therapy well, with no treatment-related mortality.
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A second retrospective single-arm study involved 20 patients with primary, unresectable
HCC who were treated with IMRT and concurrent capecitabine.(10) Patients had AJCC
grade T1 (n = 7) and T3 (n = 13) HCC. IMRT was prescribed to a minimum tumor dose
of 50 Gy in 20 fractions over 4 weeks, with the optimization goal of delivering the
prescription dose to 95% of the PTV. Capecitabine was administered as radiosensitizer
on the days of IMRT delivery. Eleven (55%) patients underwent at least 1 transarterial
chemoembolization (range: 1-3 procedures) before radiotherapy planning. Eighteen of 20
(90%) patients completed the full course of IMRT, 2 died before follow-up imaging was
obtained. The mean survival of 18 patients who completed IMRT was 9.6 months after its
conclusion. Disease progression occurred in-field in 3 patients, 2 failed elsewhere in the
liver. Four patients (25%) required hospitalization during therapy, due to encephalopathy
(n=1), gastric ulcer (n=1), acute hepatitis (n=1), and sepsis (n=1). Four required a break
from chemotherapy because of peripheral neuropathy (n=2), acute hepatitis (n=1), and
sepsis (n=1). Grade 1 acute abdominal pain was observed in 15%, 30% reported grade 1
nausea, 5% experienced grade 2 nausea. No acute or late toxicity greater than grade 2
was reported.
Pancreatic
Three reports of case series provide clinical results with IMRT for pancreatic carcinoma.
The largest series involved a retrospective analysis of 41 patients who received imageguided IMRT alone, postsurgically (41%), or with a number of concurrent primarily
fluoropyrimidine-based chemotherapy regimens (88%).(11) The prescribed radiation
dose to the PTV ranged from 41.4–60.4 Gy in daily fractions of 1.8–2 Gy. For all patients
diagnosed with adenocarcinoma (85%), 1- and 2-year actuarial OS were 38% and 25%,
respectively; median OS in resected patients was 10.8 months (range: 6.2–55.1), as
compared to 10.0 months (range: 3.4–28.0) in inoperable cases. Four patients (9.7%)
were unable to complete radiotherapy as prescribed. Any upper GI acute toxicity (none
grade 4) was reported in 29 (70%) patients, most commonly nausea, vomiting, and
abdominal pain; any lower GI acute toxicity (less than 5% grade 4) was reported in 17
(42%) cases, primarily diarrhea.
In a second series of 25 patients with pancreatic and bile duct cancers (68%
unresectable), 24 were treated with IMRT and concurrent 5FU, 1 refused
chemotherapy.(12) Resected patients received 45–50.4 Gy to the PTV, whereas
unresectable patients received 50.4–59.4 Gy. For all cancers, the median OS was 13.4
months, with 1- and 2-year OS of 55% and 22%, respectively. One- and 2-year median
OS were 83% and 50%, respectively, among resected cases, and 40% and 8%,
respectively, among unresected cases. IMRT was well-tolerated, with grade 2 or less
acute upper GI toxicity in 80% of patients; grade 4 late liver toxicity was reported in 1
patient who survived more than 5 years.
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A third retrospective series included 15 patients with pancreatic adenocarcinoma (7
resected, 8 unresectable) who underwent IMRT plus concurrent capecitabine.(13)
Resected cases received 45–54 Gy to the gross tumor volume, unresected cases received
54–55 Gy to the gross tumor volume; all cases received 45 Gy to the draining lymph
node basin. At a median follow-up of 8.5 months, no deaths were reported among the
resected patients, compared to 2 deaths in the unresected cases, yielding a 1-year OS rate
of 69% among the latter. No grade 4 toxicities were reported, with the vast majority of
acute toxicities reported at grade 1 (nausea, vomiting, diarrhea, neutropenia, anemia).
Gynecologic
A series of reports from a single institution provided data on clinical outcomes achieved
with IMRT in women with gynecologic malignancies. Patients from an initial series(14)
were included in a subsequent report that comprised 40 patients who underwent IMRT to
treat cancers of the cervix, endometrium, and other sites (3 patients).(15) Patients in this
series underwent postsurgical IMRT (70%), with (58%) or without (42%) cisplatin
chemotherapy, with a majority (60%) also undergoing postradiotherapy intracavitary
brachytherapy (ICB). IMRT was prescribed to the PTV at a dose of 45 Gy, delivered in
1.8 Gy daily fractions; ICB delivered an additional 30–40 Gy to cervical cancer patients
and 20–25 Gy to those with endometrial cancer. A well-matched nonconcurrent cohort of
patients who underwent 4-field CRT (45 Gy to the PTV, 1.8 Gy daily fractions) using 3D
planning and received cisplatin chemotherapy was used to compare acute GI and
genitourinary (GU) toxicities between radiotherapy modalities. No grade 3 acute GI or
GU toxicities were reported in IMRT or CRT recipients. Grade 2 GI toxicity was noted in
60% of the IMRT cohort versus 91% of the CRT group (p=0.002). No significant
differences were noted in the incidence of grade 2 GU toxicity in IMRT recipients (10%)
compared to the CRT cohort (20%). Three other reports from the same group provide
data on acute hematologic toxicity,(16) chronic GI toxicities, (17) and acute GI
toxicities(18) among patients who underwent IMRT with or without chemotherapy. It is
unclear whether or not the patients in these reports are those from the initial studies or are
new patients.
A small case series involved 10 patients who underwent IMRT with intracavitary
brachytherapy boost for locally advanced (FIGO stage IIB and IIIB) cervical cancer.(19)
During radiotherapy, all patients received cisplatin. Whole pelvic IMRT was
administered to a dose of 50.4 Gy in 28 fractions, and intracavitary brachytherapy (ICB)
was delivered to a dose of 30 Gy in 6 fractions. The mean OS was 25 months (range: 327 months), with actuarial OS of 67%. Acute toxicities included 1 patient with grade 3
diarrhea, 1 with grade 3 thrombocytopenia, and 3 with grade 3 leukopenia. One case of
subacute grade 3 thrombocytopenia was noted. These data are insufficient to draw
conclusions about the efficacy or safety of IMRT in cervical cancer.
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Two subsequent studies examined the use of post-hysterectomy radiotherapy in women
with high-risk cervical cancer. In the first study, 68 patients were treated with adjuvant
pelvic radiotherapy, high dose-rate ICB, and concurrent chemotherapy.(20) The initial 35
cases received 4-field box CRT delivered to the whole pelvis; a subsequent 33 patients
underwent IMRT. All patients received 50.4 Gy of radiation in 28 fractions and 6 Gy of
high dose-rate vaginal cuff ICB in 3 insertions; cisplatin was administered concurrently
to all patients. All patients completed the planned course of treatment. At median followup of 34.6 months (range: 12–52) in CRT recipients and 14 months (range: 6–25) in
IMRT recipients, the 1-year locoregional control rate was 94% for CRT and 93% for
IMRT. Grades 1 to 2 acute GI toxicities were noted in 36% and 80% of IMRT and CRT
recipients, respectively (p=0.00012), while acute grade 1 to 2 GU toxicities occurred in
30% versus 60%, respectively (p=0.022). There was no significant difference between
IMRT and CRT in the incidence of acute hematologic toxicities. Overall, the IMRT
patients had lower rates of chronic GI (p=0.002) toxicities than the CRT patients.
A subsequent report from the same group included the initial 33 patients in that
experience with an additional 21 cases.(21) At a median follow-up of 20 months, this
study showed a 3-year disease-free survival rate of 78% and an OS rate of 98% in IMRT
recipients.
Anorectal
A single-institution series included 17 patients with stage I/II cancer who underwent
IMRT alone (n=3) or concurrent with 5FU alone (n=1) or 5FU with mitomycin C (MMC,
n=13).(22) Patients generally received 45 Gy to the PTV at 1.8 Gy per fraction, followed
by a 9 Gy boost to the gross tumor volume. Thirteen of 17 (76%) patients completed
treatment as planned. None experienced acute or late grade 3 or above nonhematologic
(GI or GU) toxicity. Grade 4 acute hematologic toxicity (leukopenia, neutropenia,
thrombocytopenia) was reported in 5 of 13 (38%) patients who received concurrent
chemoradiotherapy. At a median follow-up of 20.3 months, the 2-year OS rate was 91%.
A multicenter series included a cohort of 53 consecutive patients who received
concurrent chemotherapy and IMRT.(23) Forty-eight (91%) received 5FU plus MMC,
the rest received other regimens not including MMC. Radiation was delivered at 45 Gy to
the PTV. Thirty-one (58%) patients completed therapy as planned, with breaks in the
others because of grade 4 hematologic toxicities (40% of patients), painful moist
desquamation, or severe GI toxicities. At the18-month follow-up, the local tumor control
rate was 83.9% (range: 69.9–91.6%), with an OS rate of 93.4% (range: 80.6–97.8%).
Univariate analyses did not reveal any factors significantly associated with tumor control
or survival rates, whereas a multivariate analysis showed patients with stage IIIB disease
experienced a significantly lower colostomy-free survival (hazard ratio 4.18; 95% CI:
1.062–16.417; p=0.041).
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A gastrointestinal toxicity study was reported in 45 patients who received concurrent
chemotherapy and IMRT for anal cancer.(24) Chemoradiotherapy is becoming the
standard treatment for anal cancer, in part due to preservation of sphincter function.
Patients had T1 (n=1), T2 (n=24), T3 (n=16), and T4 (n=2) tumors; N stages included Nx
(n=1), N0 (n=31), N1 (n=8), N2 (n=3), and N3 (n=2). Concurrent chemotherapy
primarily comprised 5-FU plus mitomycin C (MMC). IMRT was administered to a dose
of 45 Gy in 1.8 Gy fractions, with areas of gross disease subsequently boosted with 9–
14.4 Gy. Acute genitourinary toxicity was grade 0 in 25 (56%) cases, grade 1 in 10 (22%)
patients, grade 2 in 5 (11%) patients, with no grade 3 or 4 toxicities reported; 5 (11%)
patients had no genitourinary tract toxicities reported. Grades 3-4 leukopenia was
reported in 26 (56%) cases, neutropenia in 14 (31%), and anemia in 4 (9%). Acute GI
toxicity included grade 0 in 2 (4%) patients, grade 1 in 11 (24%), grade 2A in 25 (56%),
grade 2B in 4 (9%), grade 3 in 3 (7%) and no grade 4 toxicities. Univariate analysis of
data from these patients suggests a statistical correlation between the volume of bowel
that received 30 Gy or more of radiation and the risk for clinically significant (grade 2 or
higher) GI toxicities.
A retrospective analysis of toxicity and disease outcomes associated with IMRT was
performed in 47 patients with anal cancer.(25) Thirty-one patients had squamous cell
carcinoma (SCC). Patients had AJCC stage I (n=6, 13%), stage II (n=16, 36%), stage III
(n=14, 31%), stage IV (n=6, 13%), or recurrent disease (n=3, 7%). IMRT was prescribed
to a dose of at least 54 Gy to areas of gross disease at 1.8 Gy per fraction. Forty patients
(89%) received concurrent chemotherapy with a variety of agents including MMC, 5FU,
capecitabine, oxaliplatin, etoposide, vincristine, doxorubicin, cyclophosphamide, and
ifosfamide in various combinations. The 2-year actuarial OS for all patients was 85%.
Eight patients (18%) required treatment breaks. Toxicities included grade 4 leukopenia
(7%) and thrombocytopenia (2%); grade 3 leukopenia (18%) and anemia (4%); and,
grade 2 skin (93%). These rates were much lower than previous trials of chemoradiation,
where grade 3 to 4 skin toxicity was noted in about 50% of patients and grade 3 to 4 GI
toxicity noted in about 35%. In addition, the rate of treatment breaks was lower than in
many studies; and some studies of chemoradiation include a break from radiation
therapy. Some investigators believe that treatment breaks reduce the efficacy of this
combined approach. .
A small (n=6) case series of IMRT and concurrent infusional 5FU plus cisplatin was
reported in patients with anal cancer and para-aortic nodal involvement.(26) IMRT was
delivered to a median dose of 57.5 Gy to the CTV, with nodal areas of involvement
treated to a median dose of 55 Gy. Five of 6 completed the entire prescribed course of
IMRT. The 3-year actuarial OS rate was 63%. Four patients developed grade 3 acute
toxicities that included nausea and vomiting, diarrhea, dehydration, small bowel
obstruction, neutropenia, anemia, and leukopenia. Five of 6 had grade 2 skin toxicity.
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Input from Academic Medical Centers and Physician Specialty Societies
In response to requests, input was received from one physician specialty society (4
reviewers) and 3 academic medical centers while this policy was under review for August
2012. While the various physician specialty societies and academic medical centers may
collaborate with and make recommendations during this process through the provision of
appropriate reviewers, input received does not represent an endorsement or position
statement by the physician specialty societies or academic medical centers, unless
otherwise noted. The input was somewhat mixed, but there was support for use of IMRT
in a number of cancers discussed above. In general, this support was based on finding
different radiation doses to various organs based on treatment planning studies. There
was some support for the use of IMRT when currently accepted normal dose constraints
for safe delivery of radiation therapy could not be met without using IMRT.
In response to requests, input was received from one physician specialty society (2
reviewers) and 3 academic medical centers while this policy was under review for May
2010. While the various physician specialty societies and academic medical centers may
collaborate with and make recommendations during this process through the provision of
appropriate reviewers, input received does not represent an endorsement or position
statement by the physician specialty societies or academic medical centers, unless
otherwise noted. There was support for use of IMRT in a number of cancers discussed
above. In general, this support was based on finding different radiation doses to various
organs based on treatment planning studies.
Clinicaltrials.gov Database
More than two dozen Phase II or III clinical trials are recruiting patients to evaluate the
use of IMRT in gynecologic, pancreatic, colorectal, and hepatobiliary tract cancer
(available online at:
http://clinicaltrials.gov/ct2/results?term=imrt&recr=Open&rslt=&type=Intr&cond=anal+
OR+anorectal+OR+pelvic+OR+pancreatic+OR+gastric+OR+hepatobiliary+OR+vulval+
OR+endometrial+OR+uterine+OR+cervical&intr=&outc=&spons=&lead=&id=&state1=
&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&gndr=&phase=1&phase=2&rcv
_s=&rcv_e=&lup_s=&lup_e=).
Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) Guidelines
The guidelines for anal carcinoma
(http://www.nccn.org/professionals/physician_gls/PDF/anal.pdf, V.1.2013) state that
IMRT “may be used in place of 3D conformal RT in the treatment of anal carcinoma;”
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and, that “Its use requires expertise and careful application to avoid reduction in local
control probability.”
The guidelines also indicate that IMRT remains investigational for gastric cancer
(http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf, V.2.2012). However,
according to the NCCN, “IMRT may be appropriate in selected cases to reduce dose to
normal structures such as heart, lungs, kidneys and liver. In designing IMRT plans for
structures such as the lungs, attention should be given to the volume receiving low to
moderate doses, as well as the volume receiving high doses.”
In cervical cancer (http://www.nccn.org/professionals/physician_gls/PDF/cervical.pdf,
V.1.2012), the guidelines mention that IMRT is “becoming more widely used” but issues
with reproducibility, immobilization and definition of target “remain to be validated.”
Although IMRT is mentioned as an option in the guidelines for pancreatic
adenocarcinoma, they indicate a lack of consensus on radiotherapy dose and appropriate
setting for use of IMRT in this disease.
(http://www.nccn.org/professionals/physician_gls/PDF/pancreatic.pdf, V.2.2012).
IMRT is not mentioned in the guidelines for hepatobiliary cancers.
(http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf, V.2.2012).
IMRT is not mentioned in the guidelines for uterine endometrial cancer.
(http://www.nccn.org/professionals/physician_gls/PDF/uterine.pdf, V.3.2012).
Summary
The body of evidence available to assess the role of intensity-modulated radiation therapy
(IMRT) in the treatment of cancers of the abdomen and pelvis generally comprises case
series, both retrospective and prospective. No randomized trials have been reported that
compare results with IMRT to any other conformal radiation therapy (CRT), nor do any
of the case series include concurrently treated control patients. The available results are
generally viewed as hypothesis-generating for the design and execution of comparative
trials of IMRT versus CRT that evaluate tumor control and survival outcomes in the
context of adverse events and safety.
The comparative data on use of IMRT versus 3-dimensional conformal radiation (3DCRT) in chemoradiotherapy for anal cancer shows marked differences in rates of acute
toxicity. Thus, use of IMRT in cancer of the anus/anal canal may be considered medically
necessary.
For other tumors of the abdomen and pelvis, the evidence from treatment planning
studies has shown that the use of IMRT decreases radiation doses delivered to normal
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tissue adjacent to tumor. This potentially lowers the risk of adverse events (acute and late
effects of radiation toxicity), although the clinical benefit of reducing the radiation dose
to normal tissue using IMRT is theoretical. Due to the limitations in this evidence, this
policy underwent clinical vetting. There was support for the use of IMRT in tumors of the
abdomen and pelvis when normal tissues would receive unacceptable doses of radiation.
The results of the vetting, together with an indirect chain of evidence and the potential to
reduce harms, led to the decision that IMRT may be considered medically necessary for
the treatment of tumors of the abdomen and pelvis when dosimetric planning with
standard 3-D conformal radiation predicts that the radiation dose to an adjacent organ
would result in unacceptable normal tissue toxicity.
IMRT of the Prostate
This policy was originally created in 2008 and was regularly updated with searches of the
MEDLINE database. The most recent literature search was performed for the period of
January 2012 through March 11, 2013. The following is a summary of the key findings to
date.
As noted in the Description section, intensity-modulated radiation therapy (IMRT)
detects the areas of radiation and adjusts the dose weighting and delivery to process the
radiation plan. In contrast to 3-dimensional conformal radiotherapy (3D-CRT) that is
accurate to within 7 to 10 mm, IMRT restricts the dose and provides accuracy within 1 to
3 mm. This policy focuses on systematic reviews that evaluate outcomes of IMRT
treatment in patients with prostate cancer. This review will also summarize the data on
adverse effects from these systematic reviews and representative primary studies, given
that a reduction in adverse effects is likely to be the greatest potential benefit of IMRT.
Systematic Reviews
In 2012, Bauman and colleagues published a systematic review that examined the
evidence for IMRT in the treatment of prostate cancer in order to quantify its potential
benefits and to make recommendations for radiation treatment programs considering
adopting this technique within the province of Ontario, Canada. (1) Based on a review of
11 published reports through March 2009 (9 retrospective cohort studies and two
randomized clinical trials [RCTs]) including 4,559 patients, the authors put forth the
recommendation for IMRT over 3D-CRT for aggressive treatment of localized prostate
cancer where an escalated radiation (>70 Gy) dose is required. There were insufficient
data to recommend IMRT over 3D-CRT in the postoperative setting. (1)
Nine of 11 studies reviewed by Bauman and colleagues reported on adverse effects. Six
of 9 studies reported on acute gastrointestinal (GI) effects. (1) Four studies (3
retrospective cohort studies and 1 RCT) reported differences in adverse effects between
IMRT and 3D-CRT. The RCT included a total of 78 patients and reported that acute GI
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toxicity was significantly less frequent in the IMRT group compared to 3D-CRT. This
was true for grade 2 or higher toxicities (20% vs. 61%, p=0.001), grade 3 or higher
toxicity (0 vs. 13%, p=0.001) and for acute proctitis (15% vs. 38%, p=0.03). In contrast,
the second RCT included in this systematic review reported that there were no
differences in toxicity between IMRT and 3D-CRT. (1)
Six of 9 studies reported on acute genitourinary (GU) effects. One study, which was a
retrospective cohort study including 1,571 patients, reported a difference in overall acute
GU effects in favor of 3D-CRT (37% IMRT vs. 22% 3D-CRT, p=0.001). For late GI
toxicity, 4 of 9 studies, all retrospective cohort studies with a total of 3,333 patients,
reported differences between IMRT and 3D-CRT. One RCT reported on late GI toxicity
and did not find any differences between IMRT and 3D-CRT. Five of 9 studies reported
on late GU effects, and only one reported a difference in late GU effects in favor of 3DCRT (20% vs. 12%, p=0.01). Two retrospective cohort studies reported mixed findings
on quality-of-life outcomes. (1) A subsequent economic analysis (based on this
systematic review data) demonstrated that for radical radiation treatment (>70 Gy) of
prostate cancer, IMRT seems to be cost-effective when compared with an equivalent dose
of 3D-CRT from the perspective of the Canadian health care system for 2009. (2)
In 2008, the Agency for Healthcare Research and Quality (AHRQ) published a
systematic review comparing the relative effectiveness and safety of various treatment
options for clinically localized prostate cancer. (3) Studies on IMRT were included in the
assessment under the category of EBRT. Based on review of RCTs and nonrandomized
studies published from 2000 to September 2007, there was no direct evidence (i.e., from
RCTs) that IMRT resulted in better survival or disease-free survival than other therapies
for localized prostate cancer. Based on case-series data, the absolute risks of clinical and
biochemical outcomes (including tumor recurrence), toxicity, and quality of life after
IMRT were comparable with conformal radiation. For IMRT, the percent of patients with
grade 1 and 2 acute GI toxicity was 22% and 4%, respectively; the percent of patients
with rectal bleeding was 1.6-10%; and the percent of patients with grade 2 GU toxicity
was 28-31%. This review concluded that there was low-level evidence that IMRT
provides at least as good a radiation dose to the prostate with less radiation to the
surrounding tissues compared with conformal radiation therapy. (3)
In 2010, an update of the 2008 AHRQ systematic review was undertaken by the AHRQ
Technology Assessment Program. (4) As with the 2008 review, this review concluded
that the available data were insufficient to compare the effectiveness of the various forms
of radiation treatments. Studies on IMRT were included in the assessment under the
category of external-beam radiation therapy (EBRT) and thus reported data were not
specific to IMRT. While higher EBRT dosages may result in longer-term biochemical
control than lower EBRT dosages, overall and disease-specific survival data were
inconclusive. Additionally, GU and GI toxicities experienced with EBRT did not seem to
differ when standard fractionation was compared to moderate hypofractionization. The
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authors noted the need for further studies to evaluate outcomes of IMRT for the treatment
of prostate cancer. (4) In addition, a subsequent report undertaken by the AHRQ
Comparative Effectiveness Review Surveillance Program using the search strategy
employed for the 2008 systematic review found no new data on IMRT following a
limited literature search of the MEDLINE database through March 2012. (5)
Similar findings were observed in a systematic review of the clinical effectiveness of
IMRT for the radical treatment of prostate cancer undertaken by the U.K. Health
Technology Assessment Programme in 2010. (6) The authors also performed an
economic analysis which demonstrated IMRT to be cost-effective from the perspective of
the U,K, National Health Service for 2008/09 if this treatment modality can be used to
prolong survival. (7)
An earlier review by the Institute for Clinical and Economic Review (8) reached the
following conclusions in 2007:
“The literature on comparative rates of toxicity has serious methodological weaknesses.
There are no prospective randomized trials or cohort trials, and the case series that exist
are hampered by the lack of contemporaneous cohorts and/or by a failure to describe the
selection process by which patients were assigned to IMRT vs. 3D-CRT. Published case
series demonstrate consistent findings of a reduced rate of GI toxicity for IMRT at
radiation doses from approximately 75–80 Gy [grays]. Data on GU [genitourinary]
toxicity have not shown superiority of IMRT over 3D-CRT, nor do the existing data
suggest that IMRT provided a lower risk of erectile dysfunction.”
“The literature suggests that the risk of Grade 2 GI toxicity is approximately 14% with
3D-CRT and 4% with IMRT. Thus, the number of patients needed to treat to prevent one
case of moderate-severe proctitis is 10, and for every 100 patients treated with IMRT
instead of 3D-CRT, 10 cases of GI toxicity would be expected to be prevented.”
Primary studies reporting on outcomes and adverse effects
While the use of IMRT for prostate cancer has increased significantly, only a few
institutions have reported long-term data on biochemical control rates and toxicity. Vora
and colleagues reported on 9-year tumor control and chronic toxicities observed in 302
patients treated with IMRT for clinically localized prostate cancer at one institution. (9)
The median dose delivered was 76 Gy (range 70-77 Gy), and 35% of patients received
androgen deprivation therapy. Local and distant recurrence rates were 5% and 8.6%,
respectively. At 9 years, biochemical control rates were close to 77% for low-risk, 70%
for intermediate-risk, and 53% for high-risk patients (log rank p=0.05). At last follow-up,
only 0%/0.7% had persistent grade ≥3 GI/GU toxicity. The high-risk group was
associated with a higher distant metastasis rate (p=0.02) and death from prostate cancer
(p=0.001). (9)
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Alicikus and colleagues reported on 10-year outcomes in 170 patients treated after highdose IMRT (81 Gy). (10) The 10-year actuarial prostate-specific antigen (PSA) relapsefree survival rates were 81% for the low-risk group, 78% for the intermediate-risk group,
and 62% for the high-risk group. The 10-year distant metastases–free rates were 100%,
94%, and 90%, respectively, and cause-specific mortality rates were 0%, 3%, and 14%,
respectively. The 10-year likelihood of developing grade 2 and 3 late genitourinary
toxicity was 11% and 5%, respectively, and the likelihood of developing grade 2 and 3
late gastrointestinal toxicity was 2% and 1%, respectively. No grade 4 toxicities were
observed. These findings indicate that IMRT is associated with good long-term tumorcontrol and low rates of serious toxicity in patients with localized prostate cancer. (10)
In 2008, Zelefsky and colleagues reported on the incidence and predictors of treatmentrelated toxicity at 10 years after 3D-CRT and IMRT for localized prostate cancer. (11)
Between 1988 and 2000, 1,571 patients with stages T1-T3 prostate cancer were treated
with 3D-CRT or IMRT, with doses ranging from 66 to 81 Gy. Twenty-two percent were
considered to be at low risk, as based on National Comprehensive Cancer Network
(NCCN) guidelines. The median follow-up was 10 years. The actuarial likelihood at 10
years for the development of Grade 2 or higher GI toxicities was 9%. The use of IMRT
significantly reduced the risk of GI toxicities compared with patients treated with
conventional 3D-CRT (13% to 5%; p<0.001). Among patients who experienced acute
symptoms, the 10-year incidence of late toxicity was 42%, compared with 9% for those
who did not experience acute symptoms. The 10-year incidence of late Grade 2 or higher
GU [genitourinary] toxicity was 15%. Patients treated with 81 Gy (IMRT) had a 20%
incidence of GU symptoms at 10 years, compared with 12% for patients treated with
lower doses (p=0.01). Among patients who had developed acute symptoms during
treatment, the incidence of late toxicity at 10 years was 35%, compared with 12%. The
incidence of grade 3 GI and GU toxicities was 1% and 3%, respectively. The authors
concluded that serious late toxicity was unusual despite the delivery of high radiation
dose levels in these patients. They also noted that higher doses were associated with
increased GI and GU grade 2 toxicities, but the risk of proctitis was significantly reduced
with IMRT.
Cahlon and colleagues reported on preliminary biochemical outcomes and toxicity with
high-dose IMRT to a dose of 86.4 Gy for localized prostate cancer. (12) For this study,
478 patients were treated between August 1997 and March 2004 with 86.4 Gy using a 5to 7-field IMRT technique. The median follow-up was 53 months. Thirty-seven patients
(8%) experienced acute grade 2 GI toxicity; none had acute grade 3 or 4 GI toxicity; 105
patients (22%) experienced acute grade 2 GU toxicity; and 3 patients (0.6%) had grade 3
GU toxicity. Sixteen patients (3%) developed late grade 2 GI toxicity; 2 patients (<1%)
developed late grade 3 GI toxicity; 60 patients (13%) had late grade 2 GU toxicity; and
12 (<3%) experienced late grade 3 GU toxicity. The 5-year actuarial PSA [prostatespecific antigen] relapse-free survival, according to the nadir plus 2 ng/mL definition,
was 98%, 85%, and 70% for the low-, intermediate-, and high-risk NCCN prognostic
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groups. The authors concluded that treatment with ultra-high radiation dose levels of 86.4
Gy using IMRT for localized prostate cancer is well-tolerated., and the early excellent
biochemical control rates are encouraging. These results based on a case series should be
considered as preliminary.
In 2009, Wong and colleagues reported on a retrospective study of radiation dose
escalation in 853 patients with localized (T1c-T3N0M0) prostate cancer. (13) Radiation
therapies used included conventional dose (71 Gy) 3D-CRT (n=270), high-dose (75.6
Gy) IMRT (n=314), permanent transperineal brachytherapy (n=225), and external-beam
radiotherapy (EBRT) plus brachytherapy boost (n=44). All patients were followed for a
median of 58 months (range, 3 to 121 months). The authors reported:
“The 5-year overall survival for the entire group was 97%. The 5-year [biochemical
control] bNED rates, local control rates, and distant control rates were 74%, 93%, and
96%, respectively, for 3D-CRT; 87%, 99%, and 97%, respectively, for IMRT; 94%,
100%, and 99%, respectively, for BRT alone; and 94%, 100%, and 97%, respectively, for
EBRT + BRT. The bNED rates for 3D-CRT were significantly less than those of the
other higher dose modalities (P<.0001).”
Intermediate- and high-risk prostate cancer patients in this study had significantly
improved 5-year bNED rates with dose escalation. However, in low-risk prostate cancer
patients, bNED rates with dose escalation were not improved compared to conventional
dose 3D-CRT. The authors also found acute and late grade-2 and -3 GU toxicities were
fewer with IMRT than brachytherapy or EBRT plus brachytherapy.
Ongoing Clinical Trials
A search of online site Clinicaltrials.gov identified several Phase III randomized clinical
trials of IMRT for prostate cancer. Some trials were identified comparing IMRT to other
radiation modalities for the treatment of prostate cancer. One Phase III randomized
clinical trial is comparingIMRTto proton beam therapy to determine which therapy best
minimizes the side effects of treatment (NCT01617161). This trial has an estimated
enrollment of 461 patients and is sponsored by the Massachusetts General Hospital in
collaboration with the University of Pennsylvania and the National Cancer Institute. The
primary outcome measure is disease-free survival at 5 years. This study is currently
recruiting participants with the estimated completion date of January 2016.
In a Canadian randomized Phase III trial, 3D-CRT is being compared to helical
tomotherapy IMRT in high-risk prostate cancer patients (NCT00326638). This trial has
an estimated enrollment of 72 patients and is sponsored by the Ottawa Hospital Research
Institute. The primary outcome measure is late rectal toxicity from radiotherapy of the
prostate. This study is currently recruiting participants with the estimated completion date
of May 2014.
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In another randomized Phase III trial, hypofractionated 3D-CRT or IMRT is being
compared to conventionally fractionated 3D-CRT or IMRT in favorable-risk prostate
cancer (NCT00331773). This trial has an estimated enrollment of 1,067 patients and is
sponsored by the Radiation Therapy Oncology Group-National Cancer Institute. The
primary outcome measure is disease-free survival at 5 years. This study is currently
recruiting participants with the estimated completion date of February 2021.
A randomized ongoing Phase III trial studying the adverse effects of 3 schedules of
IMRT in treating patients with localized prostate cancer is being undertaken by the U.K.
Institute of Cancer Research (NCT00392535). This is a multicenter trial (n=26 centers)
with an estimated enrollment of 2,163 patients. The primary outcome measures are acute
and late radiation-induced side effects and freedom from prostate cancer recurrence. This
study completion date was September 2012, but final results are not published.
Preliminary results of this study have been published which report that hypofractionated
IMRT (57-60 Gy) seems equally well-tolerated as conventionally fractionated treatment
(74 Gy) at 2 years of follow-up. (14)
Summary
The evidence base for intensity-modulated radiation therapy (IMRT) of the prostate
consists largely of lower quality studies, with a lack of high-quality comparative studies
reporting on clinical outcomes. In general, where the radiation doses are similar, the
available evidence suggests that IMRT provides tumor control rates comparable to
existing radiotherapy techniques. In addition, while results are not uniform and are based
primarily on retrospective cohort trials, some studies show reductions in gastrointestinal
and genitourinary toxicity. A reduction in clinically significant complications of radiation
therapy is likely to lead to an improved quality of life for treated patients. Thus, despite
limitations in the published literature, IMRT is another technique that can be used to
deliver radiation therapy in the treatment of localized prostate cancer, and its use for this
clinical application may be considered medically necessary.
Practice Guidelines and Position Statements
The most recent National Comprehensive Cancer Network (NCCN) guidelines (v4.2011)
for prostate cancer indicate, in the principles of radiation therapy, the external-beam
radiotherapy techniques of 3-dimensional conformal (3D-CRT), or IMRT, should be
employed. (15) The NCCN guidelines also indicate 3D-CRT or IMRT may be considered
as initial treatment options in all prostate cancer patients except for patients with a verylow risk of recurrence and less than 20 years’ expected survival.
The American College of Radiology Appropriateness Criteria indicates IMRT is
appropriate for field shaping in patients being treated for clinically localized prostate
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cancer. (16) Additionally, the ACR guidelines indicate IMRT is most appropriate for
treatment planning for dose escalation
IMRT Central Nervous System Tumors
Literature Review
This policy was created in 2011 and updated with a MEDLINE literature search
performed for the period of August 2011 through February 2013. The literature on the
use of intensity-modulated radiation therapy (IMRT) in the central nervous system (CNS)
consists of dosimetry planning studies and case series; no comparative studies using
IMRT versus other conformal radiation modalities (e.g., 3-dimensional conformal
radiation [3D-CRT]) were identified.
High-grade malignant tumors
Amelio and colleagues (2010) conducted a systematic review on the clinical and
technical issues of using IMRT in newly diagnosed glioblastoma multiforme (GBM). (1)
The articles included in the review were through December 2009 and included 17 studies
(9 related to dosimetric data and technical considerations, 7 to clinical results, and 1 to
both dosimetric and clinical results) for a total of 204 treated patients and 148 patient
datasets used in planning studies. No randomized controlled studies (RCTs) were
identified, and a meta-analysis was not performed.
For the 6 papers related to planning studies that compared either 3D-CRT versus IMRT,
1 study showed a noticeable difference between 3D-CRT and IMRT for the planning
target volume (PTV) (13% benefit in V95 [volume that received 95% of the prescribed
dose] from IMRT, p<0.001) (4); the remaining studies suggested that IMRT and 3D-CRT
provide similar PTV coverage, with differences between 0 and 1%. Target dose
conformity was found to be improved with IMRT.
The organs at risk (OAR) typically under consideration in the studies were the brainstem,
optic chiasm, optic nerves, lens and retina. In general, IMRT allowed better sparing of the
OAR than 3D-CRT but with considerable variation from study to study.
The 8 studies that included clinical results included 3 retrospective, 1 prospective Phase I
and IV prospective Phase II single institution studies. Of these 8 studies, 2 used
conventional total dose and dose per fraction, 2 used a hypofractionated regimen, and in
the remaining, a hypofractionated scheme using a simultaneous integrated boost.
Chemotherapy was administered in 6 of 8 series, concomitantly with radiation and in the
adjuvant phase. Median follow-up ranged from 8.8 and 24 months. Almost all patients
(96%) were able to complete the treatment without interruption/discontinuation due to
toxicity. Acute toxicity was reported as negligible with grade-3 side effects observed in
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only 2 studies at rates of 7% and 12%. Grade-4 toxicity was recorded in only 1 series
with an absolute rate of 3%. Data for late toxicities were available in 6/8 studies, with 1
study recording grade-4 side effects with an incidence of 20%. One-year and 2-year
overall survival (OS) varied between 30% and 81.9% and between 0% and 55.6%,
respectively. When OS was reported as a median time, its value ranged from 7 to 24
months. Progression-free survival (PFS) ranged from 0% and 71.4% at 1 year and 0%
and 53.6% at 2 years. Median PFS was reported as ranging from 2.5 to 12 months.
The authors also carried out a comprehensive qualitative comparison with data reported
in the literature on similar non-IMRT clinical studies and offered the following
conclusions. The results of the planning comparisons showed 3D-CRT and IMRT
techniques provide similar results in terms of target coverage, IMRT is somewhat better
than 3D-CRT in reducing the maximum dose to the OAR, although the extent varied
from case to case, IMRT is clearly better than 3D-CRT in terms of dose conformity and
sparing of the healthy brain at medium to low doses and that (in general) there were no
aspects where IMRT seemed worse than 3D-CRT.
This evidence is limited by a number of factors. There is an absence of comparative
studies with clinical outcomes, all of the studies were small in size, from a single
institution, a majority of patients (53%) were retrospectively analyzed, and the
administration of chemotherapy was variable across studies.
A representative sample of the comparative studies on dose planning and the single-arm
studies with clinical outcomes are discussed below.
MacDonald and colleagues (2007) compared the dosimetry of IMRT and 3D-CRT in 20
patients treated for high-grade glioma. (5) Prescription dose and normal-tissue constraints
were identical for the 3D-CRT and IMRT treatment plans. The IMRT plan yielded
superior target coverage as compared with the 3D-CRT plan. The IMRT plan reduced the
percent volume of brainstem receiving a dose greater than 45 Gy by 31% (p=0.004) and
the percent volume of brain receiving a dose greater than 18 Gy, 24 Gy, and 45 Gy by
10% (p=0.059), 14% (p=0.015), and 40% (p< or=0.0001), respectively. With IMRT, the
percent volume of optic chiasm receiving more than 45 Gy was reduced by 30.4%
(p=0.047). As compared with 3D-CRT, IMRT significantly increased the tumor control
probability (p< or=0.0005) and lowered the normal-tissue complication probability for
brain and brain stem (p<0.033).
Narayana and colleagues (2006) reported the outcomes of 58 consecutive patients with
high-grade gliomas treated with IMRT. (6) GBM accounted for 70% of cases and
anaplastic gliomas for the remainder. Surgery consisted of biopsy alone in 26% of
patients and of those who underwent resection, 63% had total or near total resection and
37% had partial resection. Eighty percent of patients received adjuvant chemotherapy.
Median follow-up was 24 months. Acute neurotoxicities were grade 1/2 in 36% of
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patients, grade 3 in 7%, and grade 4 in 3%. Late toxicities were grade 1/2 in 10%, grade 3
in 7%, and no grade 4 or 5. Freedom from late neurotoxicity at 24 months was 85%.
Median OS for the anaplastic astrocytomas was 36 months and 9 months for the GBM
group. From these data, the authors concluded that the use of IMRT in high-grade
gliomas does not appear to improve survival
Narayana et al. (6) also performed a comparison of the IMRT treatment plans with 3D
plans performed in 20 patients out of 58 total in that case series. Regardless of tumor
location, IMRT did not improve PTV target coverage compared to 3D planning. IMRT
decreased the maximum dose to the spinal cord, optic nerves, and eye by 16%, 7%, and
15%, respectively. These data indicate that IMRT may result in decreased late toxicities.
Huang and colleagues (2002) compared ototoxicity with use of conventional (2D)
radiotherapy (n=11) versus IMRT (n=15) in 26 pediatric patients with medulloblastoma.
(7) All of the patients also received chemotherapy. When compared to conventional
radiotherapy, IMRT delivered 68% of the radiation dose to the auditory apparatus, but
full doses to the desired target volume. Median follow-up for audiometric evaluation was
51 months (9-107 months) for the conventional radiotherapy group and 18 months (8-37
months) for the group that received IMRT. Thirteen percent of the IMRT group had
grade-3 or -4 hearing loss, compared to 64% of the conventional radiotherapy group
(p<0.014).
Benign tumors
Milker-Zabel and colleagues (2007) reported the results of the treatment of complexshaped meningiomas of the skull base with IMRT in 94 patients. (8) Patients received
radiotherapy as primary treatment (n=26) postoperatively for residual disease (n=14) or
after local recurrence (n=54). Tumor histology was World Health Organization grade 1 in
54.3%, grade 2 in 9.6%, and grade 3 in 4.2%. Median follow-up was 4.4%. Overall local
tumor control was 93.6%. Sixty-nine patients had stable disease (by computed
tomography [CT]/magnetic resonance imaging [MRI]), and 19 had a tumor volume
reduction after IMRT. Six patients had local tumor progression on MRI a median of 22.3
months after IMRT. In 39.8% of patients, preexisting neurologic deficits improved.
Treatment-induced loss of vision was seen in 1 of 53 re-irradiated patients with a grade-3
meningioma 9 months after retreatment with IMRT.
Mackley and colleagues (2007) reported outcomes of treating pituitary adenomas with
IMRT. (9) A retrospective chart review was conducted on 34 patients treated between
1998 and 2003 at the Cleveland Clinic. Median follow-up was 42.5 months.
Radiographic local control was 89%, and among patients with secretory tumors, 100%
had a biochemical response. One patient required salvage surgery for progressive disease,
resulting in a clinical PFS of 97%. One patient who received more than 46 Gy
experienced optic neuropathy 8 months after radiation.
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Sajja and colleagues (2005) reported the outcomes of 35 patients with 37 meningiomas
treated with IMRT. (10) Tumor histology was benign in 35 and atypical in 2 tumors. The
median CT/MRI follow-up was 19.1 months (range 6.4-62.4 months). Fifty-four percent
of the meningiomas had been previously treated with surgery/radiosurgery prior to
IMRT, and 46% were treated with IMRT, primarily after a diagnosis was established by
CT/MRI. Three patients had local failure after treatment. No long-term complications
from IMRT were documented among the 35 patients.
Uy and colleagues (2002) assessed the safety and efficacy of IMRT in the treatment of
intracranial meningioma in 40 patients treated between 1994 and 1999. (11) Twenty-five
patients received IMRT after surgery either as adjuvant therapy for incomplete resection
or for recurrence, and 15 patients received definitive IMRT after a presumptive diagnosis
of meningioma on imaging. Thirty-two patients had skull base lesions and 8 had nonskull
base lesions. Follow-up ranged from 6 to 71 months (median 30 months). Defined normal
structures generally received a significantly lower dose than the target. The most
common acute CNS toxicity was mild headache, usually relieved with steroids. One
patient experienced Radiation Therapy Oncology Group (RTOG) grade-3 acute CNS
toxicity, and 2 experienced grade 3 or higher late CNS toxicity, with one possible
treatment-related death. No toxicity was observed with mean doses to the optic
nerve/chiasm up to 47 Gy and maximum doses up to 55 Gy. Cumulative 5-year local
control, PFS, and OS were 93%, 88%, and 89%, respectively.
Brain metastases
Edwards and colleagues (2010) reported outcomes on the use of whole-brain
radiotherapy (WBRT) with an IMRT boost in 11 patients with metastatic disease to the
brain ranging from 25-80 mm in maximum diameter. (3) Patients were excluded if they
had more than 4 metastases. Histologies of the metastases included primary lung (n=5),
breast (n=4), colon (n=1), and kidney (n=1). There were no acute or subacute
complications. All tumors showed response on a 1-month post-radiotherapy scan. Median
follow-up was 4 months. Four of the 11 patients died of systemic disease 6-9 months
after radiotherapy. The remaining patients were alive with no evidence of progression of
the treated brain disease or local recurrence at 2-9 months after radiotherapy. No brain
complications occurred to date.
Physician Specialty Society and Academic Medical Center Input
In response to requests in 2012, input was received related to the use of IMRT to treat
CNS tumors from 3 academic medical centers and 3 specialty medical societies (8
reviewers), for a total of 11 reviewers. While the various physician specialty societies and
academic medical centers may collaborate with and make recommendations during this
process, through the provision of appropriate reviewers, input received does not represent
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an endorsement or position statement by the physician specialty societies or academic
medical centers, unless otherwise noted.
There was near uniform consensus that IMRT to treat tumors of the CNS should be
considered medically necessary, particularly tumors in close proximity to critical
structures. Reviewers generally felt that there is sufficient evidence for IMRT being at
least as effective as 3D-conformal radiation therapy and that given the possible adverse
events that could result if nearby critical structures receive toxic radiation doses (e.g.,
blindness) that IMRT dosimetric improvements should be accepted as meaningful
evidence for its benefit.
Clinical Trials
A search of online site Clinicaltrials.gov in March 2013 returned no Phase III trials
comparing IMRT to other radiation modalities for the treatment of CNS tumors.
Summary
The body of evidence available to evaluate intensity-modulated radiation therapy (IMRT)
in the treatment of CNS tumors consists of dose planning studies and case series. The
case series are limited by small numbers, heterogeneous patient populations, and different
types of tumors. No randomized trials have been reported that compare results using
IMRT to other conformal radiation therapy modalities, nor do any of the reported case
series using IMRT include concurrently treated control groups.
In general, the limited evidence suggests that IMRT provides tumor control and survival
outcomes comparable to existing radiotherapy techniques. The evidence from treatment
planning studies has shown that the use of IMRT decreases radiation doses delivered to
critical central nervous system (CNS) structures (e.g., optic chiasm, brainstem) and
normal tissue adjacent to the tumor. This potentially lowers the risk of adverse events
(acute and late effects of radiation toxicity), although the clinical benefit of reducing the
radiation dose to critical structures and surrounding normal tissue using IMRT is
theoretical. Determination of whether adverse event rates are reduced with IMRT is
further complicated by a lack of high-quality literature defining the adverse effects using
3D-conformal radiation therapy for the CNS, the main comparator to IMRT. The singlearm case series are of limited usefulness in determining the benefits of IMRT over other
conformal radiation modalities.
Due to the limitations in this evidence, this policy underwent clinical vetting in 2012.
There was near-uniform consensus that the use of IMRT in the CNS is at least as
effective as 3D-conformal radiation therapy and that given the possible adverse events
that could result if nearby critical structures receive toxic radiation doses that IMRT
dosimetric improvements should be accepted as meaningful evidence for its benefit. The
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results of the vetting, together with a strong indirect chain of evidence and the potential to
reduce harms, led to the decision that IMRT may be considered medically necessary for
the treatment of tumors of the central nervous system that are in close proximity to
organs at risk.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network Guidelines
The National Comprehensive Cancer Network (NCCN) guidelines on Central Nervous
System Cancers state that: when radiation is given to patients with low-grade gliomas, it
is administered with restricted margins. Every attempt should be made to decrease the
radiation dose outside the target volume. This can be achieved with 3-dimensional
planning or IMRT. (12)
NCCN guidelines do not address the use of IMRT in high-grade tumors or metastases of
the CNS. (12)
V. DEFINITIONS
Top
COMPUTERIZED TOMOGRAPHY is an x-ray technique that produces a film representing a
detailed cross section of tissue structure.
INTENSITY MODULATED RADIATION THERAPY (IMRT) is an advanced form of threedimensional conformal radiation therapy (3D CRT) in which image data in the form of
computed tomography scans are used to build a 3 D model of the target organ and healthy
organs that need to be protected during therapy.
IMAGE GUIDED RADIATION THERAPY (IGRT) utilizes various imaging technologies (e.g.,
computed tomography [CT], magnetic resonance imaging [MRI], or ultrasound [US]) to
account for changes in the position of the intended target immediately before or during
treatment delivery.
VI. BENEFIT VARIATIONS
Top
The existence of this medical policy does not mean that this service is a covered benefit
under the member's contract. Benefit determinations should be based in all cases on the
applicable contract language. Medical policies do not constitute a description of benefits.
A member’s individual or group customer benefits govern which services are covered,
which are excluded, and which are subject to benefit limits and which require
preauthorization. Members and providers should consult the member’s benefit information
or contact Capital for benefit information.
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POLICY TITLE
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
POLICY NUMBER
VII. DISCLAIMER
Top
Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute
medical advice and are subject to change. Treating providers are solely responsible for medical advice and
treatment of members. Members should discuss any medical policy related to their coverage or condition
with their provider and consult their benefit information to determine if the service is covered. If there is a
discrepancy between this medical policy and a member’s benefit information, the benefit information will
govern. Capital considers the information contained in this medical policy to be proprietary and it may only
be disseminated as permitted by law.
VIII. CODING INFORMATION
Top
Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The
identification of a code in this section does not denote coverage as coverage is determined by the
terms of member benefit information. In addition, not all covered services are eligible for separate
reimbursement.
Covered when medically necessary:
CPT
Codes ®
0073T
76950
76965
77293
77301
77338
77418
77421
Current Procedural Terminology (CPT) copyrighted by American Medical Association. All Rights Reserved.
Not Medically Necessary, therefore not covered:
CPT
Codes ®
0197T
ICD-9-CM
Diagnosis
Code*
Description
140.0
Malignant neoplasm of upper lip, vermilion border
140.1
140.3
140.4
140.5
Malignant neoplasm of lip, Lower lip, vermilion border
Malignant neoplasm of lip, Upper lip, inner aspect
Malignant neoplasm of lip, Lower lip, inner aspect
Malignant neoplasm of lip, Lip, unspecified, inner aspect
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MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
140.6
140.8
140.9
141.0
141.1
141.2
141.3
141.4
141.5
141.6
141.8
141.9
142.0
142.1
142.2
142.8
142.9
143.0
143.1
143.8
143.9
144.0
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Malignant neoplasm of lip, Commissure of lip
Malignant neoplasm of lip, Other sites of lip
Malignant neoplasm of lip, Lip, unspecified, vermilion border
Malignant neoplasm of base of tongue
Malignant neoplasm of tongue, Dorsal surface of tongue
Malignant neoplasm of tongue, Tip and lateral border of tongue
Malignant neoplasm of tongue, Ventral surface of tongue
Malignant neoplasm of tongue, Anterior two-thirds of tongue, part unspecified
Malignant neoplasm of tongue, Junctional zone
Malignant neoplasm of tongue, Lingual tonsil
Malignant neoplasm of tongue, Other sites of tongue
Malignant neoplasm of tongue, Tongue, unspecified
Malignant neoplasm of parotid gland
Malignant neoplasm of major salivary glands, Submandibular gland
Malignant neoplasm of major salivary glands, Sublingual gland
Malignant neoplasm of major salivary glands, Other major salivary glands
Malignant neoplasm of major salivary glands, Salivary gland, unspecified
Malignant neoplasm of upper gum
Malignant neoplasm of lower gum
Malignant neoplasm of other sites of gum
Malignant neoplasm of gum, unspecified
Malignant neoplasm of anterior portion of floor of mouth
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MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
144.1
144.8
144.9
145.0
145.1
145.2
145.3
145.4
145.5
145.6
145.8
145.9
146.0
146.1
146.2
146.3
146.4
146.5
146.6
146.7
146.8
146.9
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Malignant neoplasm of floor of mouth, Lateral portion
Malignant neoplasm of floor of mouth, Other sites of floor of mouth
Malignant neoplasm of floor of mouth, Floor of mouth, part unspecified
Malignant neoplasm of cheek mucosa
Malignant neoplasm of Vestibule of mouth
Malignant neoplasm of Hard palate
Malignant neoplasm of Soft palate
Malignant neoplasm of Uvula
Malignant neoplasm of Palate, unspecified
Malignant neoplasm of Retromolar area
Malignant neoplasm of Other specified parts of mouth
Malignant neoplasm of Mouth, unspecified
Malignant neoplasm of tonsil
Malignant neoplasm Tonsillar fossa
Malignant neoplasm Tonsillar pillars (anterior) (posterior)
Malignant neoplasm Vallecula
Malignant neoplasm Anterior aspect of epiglottis
Malignant neoplasm Junctional region
Malignant neoplasm Lateral wall of oropharynx
Malignant neoplasm Posterior wall of oropharynx
Malignant neoplasm Other specified sites of oropharynx
Malignant neoplasm Oropharynx, unspecified
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MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
147.0
147.1
147.2
147.3
147.8
147.9
148.0
148.1
148.2
148.3
148.8
148.9
149.0-
149.1
149.8
149.9
150.0
150.1
150.2
150.3
150.4
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Malignant neoplasm of superior wall of nasopharynx
Malignant neoplasm of nasopharynx, Posterior wall
Malignant neoplasm of nasopharynx, Lateral wall
Malignant neoplasm of nasopharynx, Anterior wall
Malignant neoplasm of nasopharynx, Other specified sites of nasopharynx
Malignant neoplasm of nasopharynx, Nasopharynx, unspecified
Malignant neoplasm of postcricoid region of hypopharynx
Malignant neoplasm of hypopharynx, Pyriform sinus
Malignant neoplasm of hypopharynx, Aryepiglottic fold, hypopharyngeal aspect
Malignant neoplasm of hypopharynx, Posterior hypopharyngeal wall
Malignant neoplasm of hypopharynx, Other specified sites of hypopharynx
Malignant neoplasm of hypopharynx, Hypopharynx, unspecified
Malignant neoplasm of pharynx unspecified
Malignant neoplasm of Waldeyer's ring
Malignant neoplasm of other sites within the lip and oral cavity
Malignant neoplasm of ill-defined sites of lip and oral cavity
Malignant neoplasm of cervical esophagus
Malignant neoplasm of thoracic esophagus
Malignant neoplasm of abdominal esophagus
Malignant neoplasm of esophagus, Upper third of esophagus
Malignant neoplasm of middle third of esophagus
Page 59
MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
150.5
150.8
150.9
151.0
151.1
151.2
151.3
151.4
151.5
151.6
151.8
151.9
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Malignant neoplasm of lower third of esophagus
Malignant neoplasm of other specified part of esophagus
Malignant neoplasm of esophagus, unspecified site
Malignant neoplasm of cardia
Malignant neoplasm of pylorus
Malignant neoplasm of pyloric antrum
Malignant neoplasm of fundus of stomach
Malignant neoplasm of body of stomach
Malignant neoplasm of lesser curvature of stomach, unspecified
Malignant neoplasm of greater curvature of stomach, unspecified
Malignant neoplasm of other specified sites of stomach
Malignant neoplasm of stomach, unspecified site
154.2
Malignant neoplasm of anal canal
154.3
Malignant neoplasm of anus, unspecified site
158.0
160.0
160.1
Malignant neoplasm of retroperitoneum
Malignant neoplasm of nasal cavities
Malignant neoplasm of auditory tube, middle ear, and mastoid air cells
160.2
Malignant neoplasm of maxilary sinus
160.3
Malignant neoplasm of ethmoidal sinus
160.4
Malignant neoplasm of frontal sinus
160.5
Malignant neoplasm of sphenoidal sinus
160.8
Malignant neoplasm of other sites of nasal cavities, middle ear, and accessory
sinuses
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POLICY NUMBER
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
160.9
Malignant neoplasm of site of nasal cavities, middle ear, and accessory sinus,
unspecified site
161.0
Malignant neoplasm of glottis
161.1
Malignant neoplasm of supraglottis
161.2
Malignant neoplasm of subglottis
161.3
Malignant neoplasm of laryngeal cartilages
161.8
Malignant neoplasm of other specified sites of larynx
161.9
Malignant neoplasm of larynx, unspecified
162.0
Malignant neoplasm of trachea
162.2
Malignant neoplasm of main bronchus
162.3
Malignant neoplasm of upper lobe, bronchus, or lung
162.4
Malignant neoplasm of middle lobe, bronchus, or lung
162.5
Malignant neoplasm of lower lobe, bronchus, or lung
162.8
Malignant neoplasm of other parts of bronchus or lung
162.9
Malignant neoplasm of bronchus and lung, unspecified site
170.0
Malignant neoplasm of bones of skull and face, except mandible
170.1
Malignant neoplasm of mandible
170.2
Malignant neoplasm of vertebral column, excluding sacrum and coccyx
171.0
Malignant neoplasm of connective and other soft tissue of head, face, and neck
172.0
Malignant melanoma of skin of lip
172.1
172.2
172.3
172.4
Malignant melanoma of skin, Eyelid, including canthus
Malignant melanoma of skin, Ear and external auditory canal
Malignant melanoma of skin, Other and unspecified parts of face
Malignant melanoma of skin, Scalp and neck
173.00
Other malignant neoplasm of skin of lip
173.01
Other malignant neoplasm of skin of lip, Basal cell carcinoma of skin of lip
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MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
173.02
173.09
173.10
173.11
173.12
173.19
173.20
173.21
173.22
173.29
173.30
173.31
173.32
173.39
173.40
173.41
173.42
173.49
174.0
174.1
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Other malignant neoplasm of skin of lip, Squamous cell carcinoma of skin of lip
Other malignant neoplasm of skin of lip, Other specified malignant neoplasm of
skin of lip
Unspecified malignant neoplasm of eyelid, including canthus
Basal cell carcinoma of eyelid, including canthus
Squamous cell carcinoma of eyelid, including canthus
Other specified malignant neoplasm of eyelid, including canthus
Unspecified malignant neoplasm of skin of ear and external auditory canal
Basal cell carcinoma of skin of ear and external auditory canal
Squamous cell carcinoma of skin of ear and external auditory canal
Other specified malignant neoplasm of skin of ear and external auditory canal
Unspecified malignant neoplasm of skin of other and unspecified parts of face
Basal cell carcinoma of skin of other and unspecified parts of face
Squamous cell carcinoma of skin of other and unspecified parts of face
Other specified malignant neoplasm of skin of other and unspecified parts of face
Unspecified malignant neoplasm of scalp and skin of neck
Basal cell carcinoma of scalp and skin of neck
Squamous cell carcinoma of scalp and skin of neck
Other specified malignant neoplasm of scalp and skin of neck
Malignant neoplasm of female breast, Nipple and areola
Malignant neoplasm of female breast, Central portion
Page 62
MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
174.2
174.3
174.4
174.5
174.6
174.8
174.9
175.0
175.9
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Malignant neoplasm of female breast, Upper-inner quadrant
Malignant neoplasm of female breast, Lower-inner quadrant
Malignant neoplasm of female breast, Upper-outer quadrant
Malignant neoplasm of female breast, Lower-outer quadrant
Malignant neoplasm of female breast, Axillary tail
Malignant neoplasm of female breast, Other specified sites of female breast
Malignant neoplasm of female breast, Breast (female), unspecified
Malignant neoplasm of male breast, Nipple and areola
Malignant neoplasm of male breast, Other and unspecified sites of male breast
185.
Malignant neoplasm of prostate
190.0
Malignant neoplasm of eyeball, except conjunctiva, cornea, retina, and choroid
190.1
190.2
190.3
190.4
190.5
190.6
190.7
190.8
190.9
Malignant neoplasm of orbit
Malignant neoplasm of lacrimal gland
Malignant neoplasm of conjunctiva
Malignant neoplasm of cornea
Malignant neoplasm of retina
Malignant neoplasm of choroid
Malignant neoplasm of lacrimal duct
Malignant neoplasm of other specified sites of eye
Malignant neoplasm of eye, part unspecified
191.0
Malignant neoplasm of cerebrum, except lobes and ventricles
191.1
Malignant neoplasm of frontal lobe
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MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
191.2
Malignant neoplasm of temporal lobe
191.3
Malignant neoplasm of parietal lobe
191.4
Malignant neoplasm of occipital lobe
191.5
Malignant neoplasm of ventricles
191.6
Malignant neoplasm of cerebellum nos
191.7
Malignant neoplasm of brain stem
191.8
Malignant neoplasm of other parts of brain
191.9
Malignant neoplasm of brain unspecified
192.0
Malignant neoplasm of cranial nerves
192.1
Malignant neoplasm of cerebral meninges
192.2
Malignant neoplasm of spinal cord
192.3
Malignant neoplasm of spinal meninges
192.8
Malignant neoplasm of other specified sites of nervous system
192.9
Malignant neoplasm of nervous system, part unspecified
193
Malignant neoplasm of thyroid gland
194.1
Malignant neoplasm of other endocrine glands and related structures, Adrenal
gland
194.3
Malignant neoplasm of other endocrine glands and related structures, Pituitary
gland and craniopharyngeal duct
194.4
Malignant neoplasm of other endocrine glands and related structures, Pineal
gland
194.5
Malignant neoplasm of other endocrine glands and related structures, Carotid
body
194.6
Malignant neoplasm of other endocrine glands and related structures, Aortic body
and other paraganglia
194.8
194.9
Malignant neoplasm of other endocrine glands and related structures
Malignant neoplasm of endocrine gland, site unspecified
Page 64
MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
195.0
196.0
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Malignant neoplasm of head, face, and neck
Malignant neoplasm of Lymph nodes of head, face, and neck
197.0
Secondary malignant neoplasm of lung
198.3
Secondary malignant neoplasm of brain and spinal cord
198.4
Secondary malignant neoplasm of other parts of nervous system
200.01
200.02
200.03
200.06
200.11
200.21
200.23
200.31
200.41
200.51
200.61
200.71
200.81
201.01
201.11
201.21
Reticulosarcoma of lymph nodes of head, face, and neck
Reticulosarcoma of intrathoracic lymph nodes
Reticulosarcoma of intra-abdominal lymph nodes
Reticulosarcoma of intrapelvic lymph nodes
Lymphosarcoma of lymph nodes of head, face, and neck
Burkitt's tumor or lymphoma of lymph nodes of head, face, and neck
Burkitt's tumor or lymphoma of intra-abdominal lymph nodes
Marginal zone lymphoma, lymph nodes of head, face, and neck
Mantle cell lymphoma, lymph nodes of head, face, and neck
Primary central nervous system lymphoma, lymph nodes of head, face, and neck
Anaplastic large cell lymphoma, lymph nodes of head, face, and neck
Large cell lymphoma, lymph nodes of head, face, and neck
Other named variants of lymphosarcoma and reticulosarcoma of lymph nodes of
head, face, and neck
Hodgkin's paragranuloma of lymph nodes of head, face, and neck
Hodgkin's granuloma of lymph nodes of head, face, and neck
Hodgkin's sarcoma of lymph nodes of head, face, and neck
Page 65
MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
201.41
201.51
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Hodgkin's disease, lymphocytic-histiocytic predominance of lymph nodes of
head, face, and neck
Hodgkin's disease, nodular sclerosis, of lymph nodes of head, face, and neck
201.61
Hodgkin's disease, mixed cellularity, involving lymph nodes of head, face, and
neck
201.71
Hodgkin's disease, lymphocytic depletion, of lymph nodes of head, face, and
neck
201.91
Hodgkin's disease, unspecified type, of lymph nodes of head, face, and neck
202.01
Other malignant neoplasms of lymphoid and histiocytic tissue, Nodular
lymphoma of lymph nodes of head, face, and neck
202.11
Mycosis fungoides of lymph nodes of head, face, and neck
202.21
202.31
202.41
202.51
202.61
202.71
202.81
202.91
203.00
203.02
Sezary's disease of lymph nodes of head, face, and neck
Malignant histiocytosis of lymph nodes of head, face, and neck
Leukemic reticuloendotheliosis of lymph nodes of head, face, and neck
Letterer-Siwe disease of lymph nodes of head, face, and neck
Malignant mast cell tumors of lymph nodes of head, face, and neck
Peripheral T-cell lymphoma, lymph nodes of head, face, and neck
Other malignant lymphomas of lymph nodes of head, face, and neck
Other and unspecified malignant neoplasms of lymphoid and histiocytic tissue of
lymph nodes of head, face, and neck
Multiple myeloma, without mention of having achieved remission
Multiple myeloma, in relapse
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.
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MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
ICD 10 Effective after October 1, 2015:
ICD-10CM
Diagnosis
Code*
Description
CØØ.Ø
Malignant neoplasm of external upper lip
CØØ.1
Malignant neoplasm of external lower lip
CØØ.3
Malignant neoplasm of upper lip, inner aspect
CØØ.4
Malignant neoplasm of lower lip, inner aspect
CØØ.5
Malignant neoplasm of lip, unspecified, inner aspect
CØØ.6
Malignant neoplasm of commissure of lip, unspecified
CØØ.8
Malignant neoplasm of overlapping sites of lip
CØØ.2
Malignant neoplasm of external lip, unspecified
CØ1
Malignant neoplasm of base of tongue
CØ7
Malignant neoplasm of parotid gland
CØ3.Ø
Malignant neoplasm of upper gum
CØ4.Ø
Malignant neoplasm of anterior floor of mouth
CØ6.Ø
Malignant neoplasm of cheek mucosa
CØ9.9
Malignant neoplasm of tonsil, unspecified
C11.Ø
Malignant neoplasm of superior wall of nasopharynx
C13.Ø
Malignant neoplasm of postcricoid region
C14.Ø
Malignant neoplasm of pharynx, unspecified
C14.2
Malignant neoplasm of Waldeyer's ring
C14.8
Malignant neoplasm of overlapping sites of lip, oral cavity and pharynx
C15.3
Malignant neoplasm of upper third of esophagus
C21.1
Malignant neoplasm of anal canal
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POLICY TITLE
POLICY NUMBER
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
C21.Ø
Malignant neoplasm of anus, unspecified
C3Ø.Ø
Malignant neoplasm of nasal cavity
C31.0
Malignant neoplasm of maxillary sinus
C31.1
Malignant neoplasm of ethmoidal sinus
C31.2
Malignant neoplasm of frontal sinus
C31.3
Malignant neoplasm of sphenoid sinus
C32.1
Malignant neoplasm of supraglottis
C32.2
Malignant neoplasm of subglottis
C32.3
Malignant neoplasm of overlapping sites of larynx
C32.8
Malignant neoplasm of subglottis
C32.9
Malignant neoplasm of larynx, unspecified
C33
Malignant neoplasm of trachea
C34.00
Malignant neoplasm of unspecified main bronchus
C34.01
Malignant neoplasm of right main bronchus
C34.02
Malignant neoplasm of left main bronchus
C34.10
Malignant neoplasm of upper lobe, unspecified bronchus or lung
C34.11
Malignant neoplasm of upper lobe, right bronchus or lung
C34.12
Malignant neoplasm of upper lobe, left bronchus or lung
C34.20
Malignant neoplasm of middle lobe, bronchus or lung
C34.30
Malignant neoplasm of lower lobe, unspecified bronchus or lung
C34.31
Malignant neoplasm of lower lobe, right bronchus or lung
C34.32
Malignant neoplasm of lower lobe, left bronchus or lung
C34.80
Malignant neoplasm of overlapping sites of unspecified bronchus and lung
C34.81
Malignant neoplasm of overlapping sites of right bronchus and lung
Page 68
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POLICY TITLE
POLICY NUMBER
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
C34.82
Malignant neoplasm of overlapping sites of left bronchus and lung
C34.90
Malignant neoplasm of unspecified part of unspecified bronchus or lung
C34.91
Malignant neoplasm of unspecified part of right bronchus or lung
C34.92
Malignant neoplasm of unspecified part of left bronchus or lung
C41.Ø
Malignant neoplasm of bones of skull and face
C41.1
Malignant neoplasm of mandible
C49.Ø
Malignant neoplasm of connective and soft tissue of head, face and neck
C43.Ø
Malignant melanoma of lip
DØ3.Ø
Melanoma in situ of lip
C44.Ø
C61
Malignant neoplasm of skin of lip
Malignant neoplasm of prostate
C69.4Ø
Malignant neoplasm of unspecified ciliary body
C70.0
Malignant neoplasm of meninges, unspecified
C70.1
Malignant neoplasm of spinal meninges
C70.9
Malignant neoplasm of cerebral meninges
C71.Ø
Malignant neoplasm of cerebrum, except lobes and ventricles
C71.1
Malignant neoplasm of frontal lobe
C71.2
Malignant neoplasm of temporal lobe
C71.3
Malignant neoplasm of parietal lobe
C71.4
Malignant neoplasm of occipital lobe
C71.5
Malignant neoplasm of cerebral ventricle
C71.6
Malignant neoplasm of cerebellum
C71.7
Malignant neoplasm of brain stem
C71.8
Malignant neoplasm of overlapping sites of brain
C71.9
Malignant neoplasm of brain, unspecified
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POLICY TITLE
POLICY NUMBER
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
C72.0
Malignant neoplasm of spinal cord
C72.1
Malignant neoplasm of cauda equina
C72.5Ø
Malignant neoplasm of unspecified cranial nerve
C72.9
Malignant neoplasm of central nervous system, unspecified
C76.Ø
Malignant neoplasm of head, face and neck
C78.00
Secondary malignant neoplasm of unspecified lung
C78.01
Secondary malignant neoplasm of right lung
C78.02
Secondary malignant neoplasm of left lung
C79.31
Secondary malignant neoplasm of brain
C79.49
Secondary malignant neoplasm of other parts of nervous system
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.
IX. REFERENCES
Top
IMRT of the Breast and Lung
1. Donovan E, Bleakley N, Denholm E et al. Randomised trial of standard 2D radiotherapy
(RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast
radiotherapy. Radiother Oncol 2007; 82(3):254-64.
2. Pignol JP, Olivotto I, Rakovitch E et al. A multicenter randomized trial of breast
intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol
2008; 26(13):2085-92.
3. Violet JA, Harmer C. Breast cancer: improving outcome following adjuvant
radiotherapy. Br J Radiol 2004; 77(922):811-20.
4. Arthur DW, Morris MM, Vicini FA. Breast cancer: new radiation treatment options.
Oncology (Williston Park) 2004; 18(13):1621-9; discussion 29-30, 36-38.
5. Coles CE, Moody AM, Wilson CB et al. Reduction of radiotherapy-induced late
complications in early breast cancer: the role of intensity-modulated radiation therapy
and partial breast irradiation. Part II--Radiotherapy strategies to reduce radiationinduced late effects. Clin Oncol (R Coll Radiol) 2005; 17(2):98-110.
6. Formenti SC, Truong MT, Goldberg JD et al. Prone accelerated partial breast
irradiation after breast-conserving surgery: preliminary clinical results and dose-volume
histogram analysis. Int J Radiat Oncol Biol Phys 2004; 60(2):493-504.
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INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
7. Alonso-Basanta M MS, Lymberis S et al. Dosimetric comparisons of supine versus prone
radiation: implications on normal tissue toxicity. Int J Radiat Oncol Biol Phys 2005;
63(2 suppl1):S182-3.
8. Remouchamps VM, Vicini FA, Sharpe MB et al. Significant reductions in heart and lung
doses using deep inspiration breath hold with active breathing control and intensitymodulated radiation therapy for patients treated with locoregional breast irradiation. Int
J Radiat Oncol Biol Phys 2003; 55(2):392-406.
9. Frazier RC, Vicini FA, Sharpe MB et al. Impact of breathing motion on whole breast
radiotherapy: a dosimetric analysis using active breathing control. Int J Radiat Oncol
Biol Phys 2004; 58(4):1041-7.
10. Chang JY, Liu HH, Komaki R. Intensity modulated radiation therapy and proton
radiotherapy for non-small cell lung cancer. Curr Oncol Rep 2005; 7(4):255-9.
11. Dayes I, Rumble RB, Bowen J et al. Intensity-modulated radiotherapy in the treatment of
breast cancer. Clin Oncol (R Coll Radiol) 2012; 24(7):488-98.
12. Staffurth J. A review of the clinical evidence for intensity-modulated radiotherapy. Clin
Oncol (R Coll Radiol) 2010; 22(8):643-57.
13. Donovan EM, Bleackley NJ, Evans PM et al. Dose-position and dose-volume histogram
analysis of standard wedged and intensity modulated treatments in breast radiotherapy.
Br J Radiol 2002; 75(900):967-73.
14. Donovan EM, Yarnold JR, Adams EJ et al. An investigation into methods of IMRT
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IMRT of Abdomen and Pelvis
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5. Veldeman L, Madani I, Hulstaert F et al. Evidence behind use of intensity-modulated
radiotherapy: a systematic review of comparative clinical studies. Lancet Oncol 2008;
9(4):367-75.
6. Milano MT, Garofalo MC, Chmura SJ et al. Intensity-modulated radiation therapy in the
treatment of gastric cancer: early clinical outcome and dosimetric comparison with
conventional techniques. Br J Radiol 2006; 79(942):497-503.
7. Boda-Heggemann J, Hofheinz RD, Weiss C et al. Combined adjuvant radiochemotherapy
with IMRT/XELOX improves outcome with low renal toxicity in gastric cancer. Int J
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8. Fuller CD, Dang ND, Wang SJ et al. Image-guided intensity-modulated radiotherapy
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92(2):249-54.
9. Jang JW, Kay CS, You CR et al. Simultaneous multitarget irradiation using helical
tomotherapy for advanced hepatocellular carcinoma with multiple extrahepatic
metastases. Int J Radiat Oncol Biol Phys 2009; 74(2):412-8.
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2005; 63(2):354-61.
23. Salama JK, Mell LK, Schomas DA et al. Concurrent chemotherapy and intensitymodulated radiation therapy for anal canal cancer patients: a multicenter experience. J
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24. Devisetty K, Mell LK, Salama JK et al. A multi-institutional acute gastrointestinal
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Central Nervous System Tumors
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2. Gupta T, Wadasadawala T, Master Z et al. Encouraging early clinical outcomes with
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radiation therapy (IMRT) in the non-surgical treatment of brain metastases. Br J Radiol
2010; 83(986):133-6.
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Real-Time Intra-Fraction Target Tracking During Radiation Therapy
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with real-time electromagnetic tracking. Int J Radiat Oncol Biol Phys 2009; 74(3):9207.
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7. Noel C, Parikh PJ, Roy M et al. Prediction of intrafraction prostate motion: accuracy
of pre- and post-treatment imaging and intermittent imaging. Int J Radiat Oncol Biol
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motion. Int J Radiat Oncol Biol Phys 2008; 71(3):801-12.
9. Sandler HM, Liu PY, Dunn RL et al. Reduction in patient-reported acute morbidity in
prostate cancer patients treated with 81-Gy Intensity-modulated radiotherapy using
reduced planning target volume margins and electromagnetic tracking: assessing the
impact of margin reduction study. Urology 2010; 75(5):1004-8.
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67(4):1088-98.
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X. POLICY HISTORY
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
Top
MP- CAC 04/25/06
5.043 CAC 6/26/07
CAC 3/25/08
J12 MAC 12/12/08
CAC 11/24/09 Consensus Review. No change in policy statement. References updated.
7-16-10 FEP Variation Revised Regarding Preauth Requirement
CAC 11/30/10 Adopt BCBSA guidelines for all IMRT indications and for real-time intrafraction target tracking. Coverage for the left breast was changed to investigational. Real time
intra-fraction target tracking is considered not medically necessary.
CAC 6/26/12 Minor revisions based on BCBSA recently vetting (3) of their IMRT
policies. Policy statements on left breast IMRT changed from not medically necessary to
may be considered medically necessary technique to deliver whole breast irradiation in
patients receiving treatment for left-sided breast cancer after breast-conserving surgery
when specific conditions have been met. Policy statement on partial breast IMRT
remains investigational. Policy statement added indicating chest wall IMRT post
mastectomy is investigational. Policy statement added indicating whole breast IMRT
may be medically necessary in large-sized breasts.
IMRT of the lung was changed from not medically necessary to medically necessary
when specific indications are met. Intensity-modulated radiation therapy (IMRT) is
considered not medically necessary as a technique to deliver radiation therapy in patients
receiving palliative treatment for lung cancer.
For CNS tumors, policy revised to state that IMRT is medically necessary when the
tumor is in close proximity to organs at risk (brain stem, spinal cord, cochlea and eye
structures including optic nerve and chiasm, lens and retina) and 3-D CRT planning is
not able to meet dose volume constraints for normal tissue tolerance.
Policy statement on head and neck cancers unchanged. Policy statement on thyroid
cancer changed-may be considered medically necessary for the treatment of thyroid
cancers in close proximity to organs at risk (esoghagus, salivary glands, and spina cord)
and 3-D CRT planning is not able to meet close volume constraints or normal tissue
tolerance.
Description section rewritten. References updated.
01/28/2013-Admin code changes-skb
CAC 9/24/13 Minor revision.
For IMRT of the abdomen and pelvis, the following changes were made:
 Policy statement changed to state that IMRT may be considered medically
necessary for all anal cancers (not limited to squamous cell carcinoma)
 Policy statement changed to state that IMRT may be considered medically
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MEDICAL POLICY
POLICY TITLE
POLICY NUMBER
INTENSITY MODULATED RADIATION THERAPY (IMRT) AND REALTIME INTRA-FRACTION TARGET TRACKING
MP- 5.043
necessary for the treatment of tumors of the abdomen and pelvis when dosimetric
planning predicts the volume of small intestine receiving doses >45 Gy with
standard 3-D conformal radiation would result in unacceptable risk of small
intestine injury
 Added a policy statement that IMRT would be considered investigational for all
other uses in the abdomen and pelvis..
FEP variation revised. Guidelines and Rationale added for indications.
7/18/13 Admin code review complete. rsb
08/15/13- Policy coded.
12/19/2013- New 2014 Code updates made. Novitas Solutions Local Coverage
Determination (LCD) L27515 retired.
07/10/14- Additional dx added to policy.
10/01/14- Additional dx added to policy per JN
1/1/2015 Policy retired. For management of these services please refer to the National
Imaging Associates (NIA) Radiation Oncology Manual www.radmd.com
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Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company ®,
Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the BlueCross BlueShield Association.
Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies.
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