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Emerging Technology in Cancer Treatment: Radiotherapy Modalities
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Emerging Technology in Cancer Treatment: Radiotherapy
Modalities
Review Article [1] | October 01, 2003 | Technology [2]
By James M. Hevezi, PhD [3]
This is a period of rapid developments in radiotherapy for malignant disease. New methods of
targeting tumors with computed tomography (CT) virtual simulation, magnetic resonance imaging
(MRI), and positron-emission tomography (PET) fusion provide the clinician with information
heretofore unknown. Linear accelerators (linacs) with multileaf collimation (MLC) have replaced
lead-alloy blocks. Indeed, new attachments to the linacs allow small, pencil beams of radiation to be
emitted as the linac gantry rotates around the patient, conforming to three-dimensional (3D) targets
as never before. Planning for these delivery systems now takes the form of "inverse planning," with
CT information used to map targets and the structures to be avoided. In the area of brachytherapy,
techniques utilizing the 3D information provided by the new imaging modalities have been
perfected. Permanent seed prostate implants and high-dose-rate (HDR) irradiation techniques
targeting bronchial, head and neck, biliary, gynecologic, and other anatomic targets are now
commonplace radiotherapy tools. CT-guided permanent seed implants are being investigated, and a
new method of treating early breast cancer with HDR brachytherapy via a balloon catheter placed in
the lumpectomized cavity is coming to the forefront. Newer modalities for the treatment of
malignant and benign disease using stereotactic systems and body radiosurgery are being
developed. Targeted radionuclides using microspheres that contain radioemitters and other
monoclonal antibody systems tagged with radioemitters have been recently approved for use by the
Food and Drug Administration.
This is a period of unparalleled progress in medicine, with astounding advances in approaches to
the treatment of cancer. New surgical methods using "stealth" techniques based on interactive
imaging and endoscopic approaches with less morbidity are being introduced. New drug regimens
based on novel biologic processes are rapidly being incorporated into the armamentarium of cancer
treatment and diagnosis. With the mapping of the human genome completed, can genetic attacks on
malignant disease be far behind? Not Your Father's Cobalt Treatment Unit The field of radiation
oncology has undergone no less a renaissance. In fact, more advances have been made in radiation
oncology in the past 5 to 7 years than in the previous 100+ years since the discovery of the x-ray
and radiation-emitting nuclides. The separation and specialization of radiologic imaging and radiation
oncology that occurred during the 1980s and 1990s is quickly being reversed. The new reliance on
image guidance to establish targets for radiotherapy is forcing radiation oncologists and allied
personnel to become versant in the information provided by computed tomography (CT), magnetic
resonance imaging (MRI), and positron-emission tomography (PET). More and more, radiologists are
entering the therapeutic venue with procedures such as image- guided chemoembolization and
radiofrequency-based ablative therapy.[ 1] The new targeted radionuclide therapies-monoclonal
antibody- tagged radionuclides that "seek and destroy" selective malignant cells- are being shared
by both nuclear radiology and radiation oncology.
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Virtual
Simulation One of the more important recent advances in radiotherapy has been the introduction of
CT guidance in defining solid tumor targets and the surrounding normal tissue systems that must be
excluded from radiotherapy fields. With conventional x-ray simulators and planar radiography to
image the treatment portals, bony landmarks were frequently the only markers the radiation
oncologist had to rely on in establishing the external linac beam path to the target. With virtual CT
simulation, a complete CT image set allows contouring of the target volume on each axial CT slice
along with normal tissue structures such as the spinal cord or kidneys and reformatting of the
contoured dataset into coronal, sagittal, or three-dimensional (3D) representations with full surface
information marking where the radiation beams will enter the body. Figure 1 shows several images
from such a CT-reconstructed dataset. Illustrating the power of virtual simulation, the vertex view in
this figure could not be obtained using conventional simulation techniques because a film could not
be placed in the correct orientation to obtain this view. This technology led to the introduction of 3D
conformal radiation therapy (CRT) and the use of portals that allow radiation to enter the body from
superiorinferior oblique angles-a capability that is not available with conventional imaging methods.
Dose-Volume Histograms
Computer planning systems (which calculate the dose patterns to targets so contoured in 3D) had to
"keep up" with the technologic advance afforded by CT simulation of these targets. Fortunately,
most treatment planning companies quickly developed software to import these images to
computers and accurately portray the volume dose distributions to contoured targets and normal
tissue structures. To adequately evaluate these 3D plans, a new graphic technique involving a
"dose-volume histogram" (DVH) allowed the radiation oncologist and medical physicist to "see" the
effect of selective beam blocking or small linac gantry angle changes on partial volumes being
irradiated by the radiation field portals chosen.[2] Figure 2 illustrates such a DVH for a prostate
treatment beam arrangement. The radiation oncologist can now prescribe, for example, "100% of
the dose to the target while charging the medical physicist (or dosimetrist) to calculate the 3D plan
to give only 50% of the dose to 10% or less of the volume of an adjacent critical structure." This
ability has enhanced the protection of critical structures to an extent not previously available.
Multileaf Collimation Placing lead-alloy blocks on each field each day of treatment (some plans
called for six to eight individual fields) would prove taxing to the radiotherapist charged with daily
treatment for up to 6 weeks-the time frame for radiotherapy frequently prescribed to such patients.
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Again, the linac manufacturers developed a clever solution. Instead of the rectangular collimators
that variably blocked the beams exiting the head of the linac (along with shaped lead-alloy blocks
further restricting the beam to the target), the solid tungsten collimators were "broken up" into
individual leaves that could "slide" against one another and reproduce the shape of any of the
external blocks used earlier.[3] Figure 3 is a photo of a modern linac used in radiotherapy today.
Figure 4 is a view up into the head of a multileaf collimator-equipped linac showing the leaves in the
required configuration to treat a particular target. These leaf positions are set automatically at the
treatment console; they not only relieve the therapist from hoist-
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ing heavy
blocks for each field set, but also allow greater throughput of patients undergoing radiotherapy,
some using complex portal arrangements. Computer Verification Systems
At the same time that multileaf collimation was being developed, another advance was being made
to ensure that all of the correct parameters associated with prescribed radiation treatments were
being used for each treatment fraction. Verify-and-record computer systems that evaluated all
aspects of the treatment unit (eg, linac, multileaf collimation shape, patient position, dose) were
developed to electronically ensure that all parameters were correct for each treatment delivery.[4] If
any of the parameters were not set properly, the software would not allow the radiation beam to be
energized. This represents another level of patient safety afforded to workers in the field and
enabled the confident use of more complicated radiation field arrangements. As with any
computerized control system, however, care must be taken to input the correct data initially.[5]
Stereotactic Radiosurgery The Leksell GammaKnife system for delivering large, single-fraction
doses to benign lesions was developed early on to allow neurosurgeons and radiation oncologists to
work together to control disease entities in the brain when conventional surgery was
contraindicated.[ 6] The current version of this system consists of 201 small cobalt- 60 sources, all
pointing to a common focal point upon which the target lesion will be placed using a stereotactic
localization frame. Many disease entities have been treated with this method, including trigeminal
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neuralgia, arteriovenous malformations, meningiomas, and some metastatic lesions in the brain. A
version of this technology was developed for linac-based systems by adding a "postcollimation"
cylindrical device that could aim the radiation beam at a target in the brain while the linac gantry
moved in an arc about the patient.[7] Several oblique arcs are typically used to "spread" small doses
to normal brain tissue over larger areas in order to deliver higher doses to the target. New systems
using mini- multileaf colllimators to treat similar targets are rapidly coming into vogue. These
systems and their parallel treatment planning systems can provide conformal 3D target coverage,
while keeping doses to normal brain tissue to an acceptable level.[8] Intensity-Modulated
Radiotherapy In the early 1990s, Dr. Mark Carol, a neurosurgeon, had the clever idea that the large
radiation beams being used in conventional radiotherapy could be "broken up" into many smaller
beams, each of which could be opened when an appropriate target was "in view" or closed when a
critical structure was in the beam's path.[9] This is a simple description of the first application of
intensity-modulated radiotherapy (IMRT) using photon beams. The Nomos Corporation's Peacock
delivery and planning system was developed to treat solid tumors and "paint a dose picture," much
in the same way that CT is used to present "anatomic atlas" axial views of the inside of the body. A
postcollimation device, termed the MIMiC, consists of 40 individual binary collimators (they can be
opened or closed to block the radiation beam), in two rows of 20 each. Figure 5 depicts an en face
view of the MIMiC with every other leaf open/closed. With this system, the tumor target is treated in
axial slices along the body axis by rotating the gantry in a (usually) 270o arc about the patient. At
each gantry angle, the leaves may be open or closed depending on the controlling program of the
MIMiC computer. This computer takes its instructions from a treatment plan developed earlier with a
separate sophisticated treatment planning system. Inverse Planning
In contradistinction to conventional or 3D planning computer systems that use "trial and error" to
develop the eventual plan and to a large exent are dependent on the experience and ability of the
medical physicist or dosimetrist, the thousands of potential "opening and closings" of the MIMiC
collimator varying by gantry angle are impossible to estimate from an a priori approach. Instead,
"inverse planning" was developed, which involves using the axial slice CT image data, contouring
targets, and normal tissue structures, and sending the information to a robust calculation engine to
determine the MIMiC collimator configuration at each gantry angle that would deliver the optimized
dose distribution to the target while keeping the dose to critical structures at an acceptably low
level. Several iterations of the possible configurations are calculated until the system determines the
"best" plan based on criteria selected by the medical physicist and radiation oncologist. Figure 6
shows a treatment plan developed with this inverse planning technique for a prostate carcinoma.
Note that the system allows for conformation of the radiation dose around the anterior rectal wall, a
capability not possible with conventional planning and delivery systems. This technology was initially
applied to the brain, protecting the optical chiasm from irradiation when disease entities such as
glioblastoma multiforme or meningioma were in close proximity. Because the high-dose region so
tightly conforms in 3D to the target, a slight displacement of the high-dose volume could be
dangerous to the patient. Hence, intricate immobilization devices had to be developed to ensure that
targets were in the correct place from day to day. With this system, radiation oncologists could treat
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disease
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entities like
head and neck tumors while sparing the uninvolved parotid glands (which frequently produced
xerostomia with conventional methods) and paraspinal tumors in a wraparound configuration (which
would not be possible with conventional radiotherapy methods). Subsequently, a patented device
was added to the treatment couch that
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allowed
nonaxial slices to be treated by this system. This improvement allowed higher conformality around
the target and made possible the introduction of intensity-modulated radiosurgery into the
armamentarium of radiation oncologists.[10]Medicare Reimbursement Codes
In 2000, the Centers for Medicare and Medicaid Services (CMS) approved two new reimbursement
codes covering the use of this modality for their Medicare beneficiaries and thousands of patients
across the United States. Besides covering reimbursement for the binary MIMiC collimator, CMS also
covers IMRT using dynamic multileaf collimation; ie, using the static multileaf collimation system for
constricting fields normally, but having the leaves move during radiation delivery to produce the
highly conformal dose patterns. Again, the dynamic leaf patterns are planned in advance to produce
a prescribed volume- dose pattern and move under sophisticated computer control. All of the major
linac companies produce multileaf collimators that have IMRT capability, and several companies
have add-on systems for linacs that can produce these dose distributions. The BAT System
Because the strict immobilization requirements attendant with IMRT may not be sufficient in some
anatomic locations, the Nomos Corporation developed a new tool to allow these sites to be
approached with this modality by using an ultrasound imaging technique called BAT (B-mode
acquisition and targeting). It is well known that the prostate, for example, can move from day to day
during a course of treatment. The BAT system allows an ultrasound image of the prostate gland and
other surrounding structures to be taken daily and compared to the original ultrasound pattern
linked to the CT planning dataset. If any misalignment is detected on a particular treatment fraction,
the BAT system indicates the xyz movements the patient support table must make in order to
correct that misalignment. Figure 7 shows the BAT computer display of an IMRT patient, the
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ultrasound image, and recommended table translations to bring the target into alignment.[11]
Brachytherapy Modalities
Low-Dose-Rate Brachytherapy
Probably the most well-recognized form of brachytherapy is the application of permanent radioactive
seed implants for the treatment of prostate cancer. This therapy has had a long history and is touted
as equivalent to prostatectomy for appropriate stages of the disease. A good review of this disease
and the various forms of radiotherapy for its control can be found in an article by Eng et al.[12] Using
transrectal ultrasound to guide implantation of sealed iodine-125 or palladium- 103 seeds into the
prostate is the usual approach. However, gold-198 seeds have been used, and CT guidance
techniques are being developed. At the Cancer Therapy and Research Center, we have partnered
with Marconi Medical Systems (now Philips Medical Systems) to use a novel CT guidance system to
implant recurrent tumor systems that have undergone a full course of external-beam radiotherapy
and cannot sustain further irradiation in the surrounding region. This procedure is performed on an
outpatient basis on our CT simulator using local anesthesia along needle tracks through which the
radioactive seeds are inserted into the tumor in a preplanned fashion. Figure 8 shows the device
developed at Marconi that allows these implants to be inserted. A stereotactic arm attached to the
CT gantry "knows"
where the tip
of the device is relative to the patient on the CT table. When the tip is placed on the skin surface, the
PinPoint system display screen shows the patient's CT slice images under this touch point. Figure 9
provides an example of the four-frame image display using this system. The tip also displays a
virtual needle path that can be adjusted to avoid critical structures on its way to the tumor depth.
This tip subsequently acts as a physical needle guide allowing the physician to anesthetize the
physical needle path and, thereafter, introduce permanent iodine-125 seeds into the tumor,
irradiating the recurrent neoplasm from the "inside out." Head and neck, paraspinal, abdominal, and
pelvic recurrences have been treated in this fashion at the University of Texas Health Science Center
at San Antonio. The procedure continues to be refined, and a more complete description and
rationale for its use can be found in a recent Society of Interventional Radiology syllabus.[13] Other
methods using permanent ra-
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dioactive seed
implants along with the more conventional low-dose-rate (LDR) temporary radioactive source
implants are finding their way into the radiation oncologist's "tool box" to effectively treat a myriad
of solid tumor systems. With the advent of IMRT, these LDR brachytherapy systems will have
competition to limit the dose to the tumor only. They may, however, have some interesting
radiobiologic advantages over IMRT methods.[13] High-Dose-Rate Brachytherapy
High-dose-rate (HDR) remote afterloading systems have been used in brachytherapy for several
years. In order to reduce the exposure of personnel to radiation while they care for patients receiving
temporary brachytherapy implants, remote afterloading systems were introduced, allowing volume
doses to be delivered to patients who have had the applicators (usually catheter guides) placed in
and around the tumor in the operating room. A single, high-dose-rate emitting source (usually
iridium-192) system is connected to the catheters, and the source-under preplanned computer
control with the patient in a separate shielded room-is propelled out of its shielded container into the
catheters. The source makes preprogrammed stops, delivering the prescribed dose to the target
volume. Figure 10 shows a typical set-up for this novel approach to brachytherapy. HDR is used
extensively to treat head and neck, bronchogenic (one of its initial uses),[14] pelvic, and biliary tract
tumors. Unlike LDR brachytherapy, which is delivered in a continuous (over many days), single insult
to the tumor system (whether in a temporary or permanent regimen), HDR must be fractionated for
several separate implant settings. The radiobiology of the higher dose rate attendant with this
procedure requires this fractionation scheme.[15] This disadvantage, however, is balanced by the
ability to move the dose around "on the fly," and areas that received higher or lower doses than
planned on previous fractions can be given a homogenized dose distribution on subsequent
fractions. With CT 3D information available to treatment planners, new strides using HDR will further
enhance the application of this technology. Indeed, HDR prostate implants are being applied to
patients who either cannot or do not opt for transrectal ultrasound LDR implants or
prostatectomy.[16]
HDR in Early Breast Cancer- One of the newest uses of HDR is in early-stage breast
cancer. The latest data from the original National Cancer Institute trial comparing
mastectomy to breast-conserving therapy plus radiotherapy presented at the 2002 Breast
Cancer Symposium in San Antonio continues to demonstrate equivalent survival between the
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two arms.[17] Whole-breast irradiation of the lumpectomized breast is considered the
standard of care for this disease. Single-institution trials, however, have shown that
accelerated, partial-breast irradiation is associated with similar control statistics and relapsefree survivals.[18] Again, for early disease, the lumpectomized breast is implanted with
catheters through the volume at risk, and the patient is taken to the HDR suite for treatment.
Twice-daily fractions for 5 days deliver doses equivalent to 6 weeks of external-beam
wholebreast irradiation. Because the tissues at risk for recurrence in some forms of breast
cancer are those immediately surrounding the lumpectomized cavity, Proxima Therapeutics
has developed a novel approach to treating these tissues.[ 19] At the time of lumpectomy,
the surgeon leaves a saline-filled balloon catheter in the breast. After an appropriate
recovery period, the patient begins a course of HDR brachytherapy using the accelerated
partial-breast irradiation technique of fractionated therapy twice daily for 5 days. Figure 11
shows a CT slice through the balloon with catheter in place. The HDR source will be propelled
to the center of the balloon for treatment. Although only recently approved by the Food and
Drug Administration for this use, a National Surgical Adjuvant Breast and Bowel Project phase
III trial is being planned to compare the three approaches:
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whole-breast irradiation, catheteraccelerated partial-breast irradiation, and
balloon-catheter-accelerated partial-breast irradiation.
Intravascular Brachytherapy- Another method of applying HDR to a disease entity not
malignant by character but certainly serious by location is the administration of
single-fraction doses to the inside of coronary vessels; this post-in-stent restenotic
intervention is called intravascular or coronary artery brachytherapy.[20] Figure 12 shows
the setup of one such device for this application. It is thought that the targets of this therapy
are the growth factor centers that form scar tissue blocking the injured site from either
angioplasty or stent placement. Small, single-fraction doses of radiation seem to be effective
in preventing restenosis in this setting. Although clinical trials using drug-eluting stents in
competition with this HDR technique show promise, irradiation of these sites has proven
effective and also shows promise in preventing stenosis in peripheral vascular disease.[21]
New Paradigm of Cooperation- Teams of medical professionals seem to be assembling as
other applications of radiation medicine take hold in health care. In the case described
above, the interventional cardiologist, radiation oncologist, and medical physicist work
together to provide unparalleled care for these patients. In other venues, it is the urologist,
radiation oncologist, and medical physicist who provide the team effort. In the performance
of stereotactic radiosurgery, the neurosurgeon, radiation oncologist, and medical physicist
work together to treat the patient. This is a new paradigm for cooperation and
cross-fertilization of fields. It has never been so keenly expressed, however, as in the
therapies being offered to cancer patients (eg, combination chemotherapy and radiation
therapy). Radiation and medical oncologists have always paired their skills in attacking the
cancer problem. The most recent example of this is the addition of anticancer drug regimens
to cervical cancer therapy-a disease entity that previously had purview only in the realm of
radiation oncology.Conclusions and Future Directions
What will the immediate future bring in terms of new technologies to fight cancer? To begin
with, geometric anatomic information will be fused with functional anatomic information to
allow new targets to be established for radiotherapy. For example, Figure 13 shows the
CT/PET-fused datasets for a patient with a recurrent apical lung carcinoma. IMRT was
considered for the treatment of the apical lesion as it presented the perfect target for this
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modality. However, after the PET and CT data were fused, lymphatic spread was evident that
precluded the use of IMRT, and the patient was referred for conventional radiotherapy. MRIs
of brain lesions have been typically fused with CT datasets to set radiotherapy targets more
precisely. At least one manufacturer (Philips Medical Systems) is developing a program that
uses MRI as the primary method of establishing radiotherapy fields. Besides the use of
fluorodeoxyglucose PET functional imagery to identify targets, new PET radionuclides will be
developed that target solid tumor systems. These molecular imaging systems may even be
based on shorter-lived radionuclides, so methods of getting the tracer to the patient shortly
after production will take a fair amount of ingenuity. Of course, one can install a production
cyclotron next to the PET facility, but these units are rather expensive, and this option may
not be feasible. Perhaps combining the PET facility with a proton accelerator that may be
used in delivering proton beams for radiotherapy could be envisaged for larger cancer
centers. Indeed, there appears to be a proliferation of these proton therapy facilities. Again,
however, they are expensive and require enormous resources to develop.[22] Adaptive
Radiotherapy
Other methods of delivering highly conformal photon beams la the IMRT formula are also
being developed. The CyberKnife is a planning and delivery system that utilizes a robotic
arm, which is attached to a lowenergy, S-band linac photon accelerator.[ 23] Opposite the
photon delivery unit is a fluoroscopic system that senses the preplanned direction of the
beam. Small pencil beams of photons are "fired" at the target from virtually any 3D direction
that the robotic arm can access. This mechanism effectively limits the dose to normal tissue
while ensuring the target dose is high. As with the BAT ultrasound positioning system, the
fluoro unit is an example of a new thrust in radiotherapy called "adaptive radiotherapy."
Because, by the methods described in this article, targets must be accessed with more 3D
precision than is available in conventional radiotherapy, the onus of locating these
targets-which may move between daily fractions from the original, planned positions- is
much greater. Daily imaging and delivery are the basis of a CT unit that contains a small
photon-beam delivery system for such an adaptive radiotherapy application.[24] The
Tomotherapy Corp has delivered several of these units to radiotherapy centers, and the field
awaits the results of their studies. Adaptive radiotherapy also encompasses the application of
respiratory gating to daily conformal targeting. One must allow sufficient margins around
lung lesion targets treated with IMRT methods to keep the target in the radiation field during
sometimes large excursions caused by respiration. Because linac photon beams are
electronically produced, these beams can be pulsed on or off at will and lend themselves to
this new application. That is, the radiation beam can be turned on during expiration, for
example, and off during inspiration, effectively keeping the target in a virtual static location.
Active breathing control is another technique for keeping a target in place, in this case by
allowing the patient's breathing to be controlled during therapy.[25] Real-time imaging will
form an important part of this technology, and electronic portal imaging devices-ie,
fluoroscopic-like devices that were used initially in place of ra diation portal films-are being
used to ensure that targets are in the correct place while radiotherapy is delivered. The
future is bright for our ability to attack tumor targets that we could not even consider
approaching previously. Indeed, with these emerging technologies in radiotherapy, many
patients who pose more challenging clinical scenarios need not be turned away.
Disclosures: The author(s) have no significant financial interest or other relationship with the
manufacturers of any products or providers of any service mentioned in this article.
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py-modalities-0
Links:
[1] http://www.physicianspractice.com/review-article
[2] http://www.physicianspractice.com/technology
[3] http://www.physicianspractice.com/authors/james-m-hevezi-phd
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