May 1

Michael May

Comparative Article Analysis Part 1: Trade Magazine

When you think about the publications related to the field you work in, there are both
trade magazines and professional journals. They both have a place but are very different in
content and purpose. Trade magazines are not much different from other magazines you
would pick up off the rack but do provide entertaining and sometimes meaningful content.
When I browse through my copy of Radiology Today, the first thing I notice is bright multi-
colored cover with several different enticing headlines. When browsing through the magazine I
see many different advertisements, short articles filled with pictures, various commentary and
simple case study. The thing about trade magazines is that they make money from
advertisements, the authors are typically reimbursed, and the authors are not always experts in
the field that they are writing about1. As I browsed this magazine an article caught my eye
because I am always interested in what up and coming technology is making its way out. Real
Time Radiotherapy, an article written by freelance medical writer Beth W. Orenstein, is a nice
introduction to the upcoming MRI guided radiotherapy units coming to market in the next year
or two.

Orenstein does a great job of introducing the technology of MRI guided radiotherapy
and informs the reader that there will be units offered by ViewRay and Elekta by next year 2.
Instead of comparing the two units, Orenstein chooses to give the reader a brief history of the
challenges of bringing this type of unit to market and how some of the technical obstacles were
overcame. The current unit on the market uses a modified MRI so that the magnetic field does
not disturb the flow of electrons during treatment. Orenstein does a great job of adding
credibility to the article by quoting physicians and other professionals in the field. She goes on
to explain the benefits of using an MRI guided radiotherapy unit by explaining how we as
providers could monitor the target volume in real time to provide better treatment to highly
mobile tumors. Physicians could also make decisions to up doses, lower doses, or change
fractionation based on real time monitoring of tumor resistance or susceptibility. Orenstein
concludes with a brief summary of cost vs. benefits of this new technology. By quoting another
professional we learn that this is not intended to be a piece of equipment but could really
benefit about 25% of the people receiving radiation therapy. The cost is expected to be much
greater than traditional radiotherapy, but could be a significant benefit to many people,
especially if the cost comes down or reimbursement is raised.
 May 2

I did find this article interesting and did learn a few things about a technology I have
previously read about. I am not convinced that this article will benefit most people though.
Beyond informing people that this technology exists, it seems like the technology will be out of
reach to most clinics. The equipment is highly specialized, will take specially trained people,
and only benefit a small population of people. The cost will most likely keep clinics away from
this for at least the near future. I feel the strength of this article lies in the supporting
testimony she included while explaining the major benefits to the patients and the doctors
using the equipment. I had trouble finding fault in the article for the average reader but I feel
that it brings up many new questions for a professional. Several explanations were vague on
how they could benefit someone, especially the use more technical things such as diffuse
weighted MRIs. My peer review article will address this question.
 May 3

References

1. Lenards N, Weege M. Reading & Writing in Radiation Therapy &Medical Dosimetry.

[SoftChalk]. La Crosse, WI: UW-L Medical Dosimetry and Radiation Therapy Program;

2016.

2. Orenstein B. (2017, January). Real Time Radiotherapy. Radiology Today, (18), 1, 16-19.
 May 4

Comparative Article Analysis Part 2: Peer Reviewed Journal

Peer reviewed journal articles are very different than trade magazine articles. At first
glance you will notice that a peer reviewed journal article is highly structured and predictable in
formatting. A peer review journal does not pay its contributors; in fact, most contributors are
paying for a chance to be published1. That is because publishing in a peer reviewed journal is a
prestigious event that shows you have contributed to the growing amount of research in your
field. These journals are very specialized and you typically cannot be published without a group
of peers reviewing your work and finding it worthy of print. The writing style is scientific and
you will see that original research predominantly fills the pages of a peer review journal. As a
good comparison, I chose to evaluate an article referenced in the trade magazine article I
reviewed earlier. Longitudinal diffusion MRI for treatment response assessment: Preliminary
experience using an MRI-guided tri-cobalt 60 radiotherapy system by Yang Y, Cao M, Sheng K,
et al. was a study done at UCLA using the previously discussed MRI guided radiotherapy
equipment.

Yang Y, et al proposed using the MRI guidance on the MRI guided radiotherapy unit to
perform diffusion weighted MRIs periodically during treatment to test the feasibility of
evaluating patient response to treatment in real time2. Diffusion weighted MRI can help
physicians evaluate tumor response by identifying biologic characteristics of tumors3. By using
the apparent diffusion coefficient (ADC) physicians are able to correlate the treatment to
relative tumor control and patient outcomes2. The research team was able to test this by
performing diffusion weighted MRIs every 2-5 fractions on 6 different patients. The
researchers used tumor volumes that were expected to change as well as reference points on
each patient that were expected to stay constant. Phantom verification was performed as well
to confirm that measurements of ADC values were accurate. A decrease in ADC would indicate
tumor response to treatment. The researchers were able to conclude that diffusion MRI could
be a great way to monitor patients during treatment for tumor response. The researchers were
able to accurately evaluate patients for tumor response and in 1 case resistance. The
researchers acknowledge that the sample size was very small but that they conclude that a
larger study would be a worthwhile endeavor. The implications of this research are great.
Being able to monitor tumor response to treatment in real time would allow physicians to
practice adaptive therapy. This means a physician could choose to reduce dose, increase dose,
change fractionation, and try different concomitant chemotherapy among other things.
Despite the small sample, I believe the research was well done. Phantoms were used to make
sure data was accurate, control points in the patient were measured for consistency, the data
 May 5

was summarized well and easy to follow, and I do not believe any bias affected this study. My
only concern would be the way in which the 6 participants were chosen for the study, there is
no mention of this process. The authors referenced 18 different sources that were all recently
published as well.
 May 6

References

1. Lenards N, Weege M. Reading & Writing in Radiation Therapy &Medical Dosimetry.

[SoftChalk]. La Crosse, WI: UW-L Medical Dosimetry and Radiation Therapy Program;

2016.

2. Yang Y, Cao M, Sheng K, Gao Y, Chen A, Kamrava M, Lee P, Agazaryan N, Lamb J,

Thomas D, Low D. Longitudinal diffusion MRI for treatment response assessment:
Preliminary experience using an MRI-guided tri-cobalt 60 radiotherapy system. Med.
Phys. 43(3), March 2016.
3. Park M, Cha E, Kang B, Ihn Y, Baik J. The Role of Diffusion-Weighted Imaging and the
Apparent Diffusion Coefficient (ADC) Values for Breast Tumors. Korean J Radiol. 8(5),
October 2007.
January 2017

Real-Time Radiotherapy
By Beth W. Orenstein
Radiology Today
Vol. 18 No. 1 P. 16

MRI has the potential to improve the efficacy of radiation oncology.

What if radiation oncologists could see tumors and surrounding normal tissue as they were treating them in real time?
"It may result in a revolutionary change in our field," says John Christodouleas, MD, MPH, a radiation oncologist and
vice president of medical affairs and clinical research at Elekta, one of two companies that are introducing MRI-
guided radiation therapy systems to the market.

Elekta, based in Stockholm, Sweden, plans to take its first commercial orders for its high-field MR-linac, an MRI-
guided linear accelerator, in 2017 with deliveries in 2018, assuming it receives the applicable regulatory clearances.
Cleveland-based ViewRay, which nearly three years ago introduced the world's first clinical MRI-guided radiation
therapy system using cobalt sources, is now introducing a linear accelerator version of its system, the MRIdian Linac.
The MRIdian Linac is for sale and clinical use in Europe and for nonclinical research in the United States, while the
company pursues 510(k) approval from the FDA. Some cancer centers in the United States hope to have ViewRay's
MRIdian Linac operational later this year.

Long Time Coming

Twenty years ago, radiation oncologists used a combination of skin marks and plain film X-rays to guide radiation
treatments in cancer patients. Since the early 2000s, radiation oncologists have been using cone beam CT to align
treatment to tumors.
"Cone beam CT transformed the clinician's ability to see where they are putting the radiation," says Kevin Brown,
Elekta's global vice president of scientific research. But it doesn't go far enough. "There still are a lot of targets you
cannot see on CT because there isn't sufficient contrast," Brown says. MR is much better at seeing soft tissues and
enables physicians to "actually put radiation where they want to put it, not where they think they should put it."

The combination MR scanner and linear accelerator has been at least 16 years in the making, Brown says. "That's
when the concept for the machine was conceived at our research partner, UMC Utrecht."

The challenge for physicists was to find a way to deliver radiation treatment in the presence of a strong magnetic
field. Radiotherapy treatment is typically done with a linear accelerator, which generates high-energy X-rays.
Physicists had to find a way to stop the electrons that the radiation beams' photons generate from being diverted by
the MRI's magnetic field. Their solution was to modify the MRI in a special way so the electrons wouldn't be affected
by its magnetic field. The linear accelerator is mounted on a rotating gantry so that the treatment beam can pass
directly through the body of the MRI, enabling the patient to be imaged and treated simultaneously.

Another issue was stopping leaks that create noise and interfere with the MR images. To solve this problem,
ViewRay researchers took a cue from the military, which has learned how to hide airplanes from radar, says Jim
Dempsey, PhD, ViewRay's founder and chief scientific officer. Stealth aircraft are coated in carbon, which absorbs
microwaves. Copper reflects microwaves. In its patented technology, "we use layers of copper and carbon shielding
to meet up and absorb any leaking radiofrequency interference," Dempsey says.

Personalized Therapy
The MRI-guided linear accelerator can be used to treat all types of cancer at almost all locations, says Ben J.
Slotman, MD, PhD, a professor and chairman of the department of radiation oncology at Vrije University Medical
Center in Amsterdam. "We have the MRIdian system in use for six months now and have focused on patients with
tumors in the pancreas, liver, adrenal gland, kidney, prostate, rectum, lung, and breast. In all these cases, we use
stereotactic or hypofractionated treatment. However, if we have free time slots available, we also use it for some
other indications."

The MR-linear accelerator combination could solve several challenges that radiation oncologists currently face. One
of the huge challenges is not being able to predict when a healthy organ exhibits severe toxicities from radiation,
Christodouleas says. "One reason is that human beings are different in the way they are sensitive to radiation," he
says. Some patients are just more sensitive than others. "Another reason is that we really don't know what dose
normal tissues have gotten over the course of treatment. We don't have good ways of tracking that." One of the major
benefits of having superior soft tissue imaging during treatment "is that it can help us target and track the cumulative
dose to both tumor and healthy tissues over the course of therapy," he says.

The combination system also allows radiation oncology to be tailored to the patient's tumor. "The way most radiation
treatment works is you create a plan in advance, and you deliver that exact same plan without changing it," says
Michael F. Bassetti, MD, PhD, a radiation oncologist at the University of Wisconsin's Carbone Cancer Center in
Madison, one of the first centers to treat with ViewRay's low-field system, beginning in 2014.

"[The MR-linear accelerator] allows the potential to adjust the treatment as you go along based on response. It really
offers potential useful information about the patient's individual cancer biology and the ability to personalize the
treatment" vs one-size-fits-all treatments, he says. "With good quality imaging on a daily basis, we can actually watch
the response as it is happening during their treatment course and make adjustments, if we want," Bassetti says.

In the future, MR-linear accelerator systems may allow oncologists to decide whether a patient benefits from further
treatment based on the in-treatment imaging response. "For example, some patients may have such a good
response that they may not need surgery, while poor responders might need more aggressive surgery or
chemotherapy as a follow-up," he says.

Better Dose Control

While the MR-linear accelerators can be used for most tumors, those using it find it is most helpful for tumors in
locations that can change from day to day because of movement of nearby organs. Good examples are tumors of the
lung, which can move with each breath, and tumors of the abdomen that can be affected by how full the patient's
bowel or bladder are. Today, Slotman says, physicians are able to control around 90% of early-stage lung cancers
with stereotactic ablative radiotherapy. With the MRIdian Linac, the radiation oncologists could push their success
rate even higher because they can see the lung tumor as it moves up and down with each breath. Knowing where the
tumor is during treatment means they can deliver the radiation only when it is in the target field, he says.

The system is also ideal for treating tumors such as those found on the pancreas that are close to critical sensitive
structures, Bassetti says. The pancreas lies in very close proximity to the small intestine, stomach, kidneys, and
spinal cord. Many patients' tumors are adjacent to organs, such as the intestine or stomach, that cannot tolerate high
doses of radiation, Bassetti says. "So the doses of radiation we would like to deliver are limited by our ability to avoid
that dose to critical or adjacent organs. If we can see what we're doing, while we're doing it, we understand what
we're delivering to that organ."

The combination system also could lead to higher radiation dosing, if it is needed, for a number of reasons. One
reason is physicians don't have to be concerned about delivering such high doses to healthy tissue because they can
clearly see when it is and isn't in the way, Brown says. "I'm much more comfortable giving a very high dose of
radiation to a tumor if I can see the intestine right next to it and know it isn't moving into the field," Bassetti agrees.

Treatment Response and Planning

Also, if physicians can image the patient during treatment, as opposed to before and after, they can see how well the
treatment is working as they are delivering it. They might need to step up the dose if the tumor isn't responding, or
they could perhaps lower the dose or number of treatments if they see it's responding well after only a few of the
planned courses. In most cases, radiation oncologists have to wait three months or more after treatment to reimage
their patients and see how well they responded.

In the future, Brown says, physicians will be able to use MRI diffusion weighted imaging to determine the
effectiveness of the treatment as they are delivering it. "There are many things MR sequences can show you," he
explains, "and one will tell you about the diffusion of water in tissue. That can tell you how densely packed the tissues
are at the cellular level. If water is able to diffuse more readily between cells, that's a sign that there's tissue death.
That's something we wouldn't be able to pick up before."

Researchers at UCLA reported in the March 2016 issue of Medical Physics on their pilot study using ViewRay's
MRI-guided radiotherapy system to perform a longitudinal diffusion MRI strategy for assessing patient response to
radiotherapy. They concluded that such an approach may enable response-guided adaptive radiotherapy, but more
research is needed.
Eventually, Christodouleas says, researchers hope to automate the best sequences for different types of tumors and
treatments based on experience with the combination machine. MR imaging should help, for example, to identify
organs and their parts. With that information, "we may find that you need one sequence for a pancreatic tumor that's
up against the duodenum and another for a tumor that's midpancreas and not constantly up against the bowel," he
says. "It's not a question of whether it can be done with the MR images. It's really just a matter of putting these
sequences together. In a CT world, you're still just getting the one parameter, and you simply can't solve these
problems."

Another potential advantage is shortening time to treatment, especially when radiation therapy is being used for
palliative care, Bassetti says. Now, patients have to come to radiology for a CT scan to plan their treatment. "We
send them away or back to the hospital floor while we plan the radiation," he says. "With this system, you can plan on
the fly entirely, so we can bring them down for one single visit, potentially." It not only is more convenient for the
patient but also allows them to get the pain relief they need sooner, he says.

Costs vs Benefits
While combining MR and linear accelerators has many advantages, it also has some disadvantages. One
disadvantage to the MRI-linear accelerator is that it is likely more expensive than regular radiotherapy. Radiotherapy
is incredibly low-cost compared with chemotherapy or surgery or other techniques used for cancer treatment, Brown
says. Radiotherapy has benefitted from efficiencies that continue to lower its cost, he says. "Using the MR-linac will
likely be more expensive," Brown says. Reimbursement could also be an issue. "One of the things we will be looking
at is enhanced reimbursement for the MR-linac. We believe, if it brings value to the health care system, our users
should be reimbursed accordingly," he says.

Time also could be a disadvantage. A regular session using the MR-linac shouldn't take any longer than a session
with a conventional linear accelerator, Brown says. However, using diffusion weighted imaging to determine tumor
response could add some time to treatment sessions. Typically, radiation sessions last 15 to 20 minutes. Diffusion
weighted imaging may add five to 10 minutes. "So you're not really talking about a significant amount of time,
especially compared to the potential benefit," Brown says.

In addition, some patients have metal implants and cannot get MRIs, Bassetti says. Also, there's this: While MR is
nonionizing and there's no safety concern for exposing patients to any unnecessary radiation, a strong magnet
requires that proper safety procedures be put in place. Elekta uses a 1.5T MR imaging system from Philips similar to
that used in its diagnostic systems.

Those familiar with the MRI-linear accelerator machines don't believe they will ever be the standard treatment for all
cancers, but Slotman believes that if cost weren't an issue, more patients would be treated with them. "I believe that
15% to 25% of patients who are treated with radiotherapy will have a definite benefit of MR-guided radiotherapy," he
says. "If costs were not an issue, this could easily be 80% to 90%."

Because it's more expensive, it won't be used for cases that don't require it, Brown agrees. "It would make sense to
treat those cases on the less expensive technology that is still of high quality." However, Brown says, it's all about
"seeing," and "seeing" what the radiation oncologists are doing as the treatment happens can make all the difference.

"This has the potential to improve the efficacy of radiation therapy," Dempsey agrees, and that can be life-changing
for some patients.

Beth W. Orenstein, of Northampton, Pennsylvania, is a freelance medical writer and regular contributor to
Radiology Today.
Longitudinal diffusion MRI for treatment response assessment: Preliminary
experience using an MRI-guided tri-cobalt 60 radiotherapy system
Yingli Yang,a) Minsong Cao, Ke Sheng, Yu Gao, Allen Chen, Mitch Kamrava, Percy Lee,
Nzhde Agazaryan, James Lamb, David Thomas, and Daniel Low
Department of Radiation Oncology, University of California, Los Angeles, California 90095

Peng Hu
Department of Radiological Sciences, University of California, Los Angeles, California 90095

(Received 7 December 2015; revised 3 February 2016; accepted for publication 6 February 2016;
published 23 February 2016)
Purpose: To demonstrate the preliminary feasibility of a longitudinal diffusion magnetic resonance
imaging (MRI) strategy for assessing patient response to radiotherapy at 0.35 T using an MRI-guided
radiotherapy system (ViewRay).
Methods: Six patients (three head and neck cancer, three sarcoma) who underwent fractionated
radiotherapy were enrolled in this study. A 2D multislice spin echo single-shot echo planar imaging
diffusion pulse sequence was implemented on the ViewRay system and tested in phantom studies.
The same pulse sequence was used to acquire longitudinal diffusion data (every 25 fractions) on the
six patients throughout the entire course of radiotherapy. The reproducibility of the apparent diffusion
coefficient (ADC) measurements was assessed using reference regions and the temporal variations of
the tumor ADC values were evaluated.
Results: In diffusion phantom studies, the ADC values measured on the ViewRay system matched
well with reference ADC values with <5% error for a range of ground truth diffusion coefficients
of 0.41.1 103 mm2/s. The remote reference regions (i.e., brainstem in head and neck patients)
had consistent ADC values throughout the therapy for all three head and neck patients, indicating
acceptable reproducibility of the diffusion imaging sequence. The tumor ADC values changed
throughout therapy, with the change differing between patients, ranging from a 40% drop in ADC
within the first week of therapy to gradually increasing throughout therapy. For larger tumors,
intratumoral heterogeneity was observed. For one sarcoma patient, postradiotherapy biopsy showed
less than 10% necrosis score, which correlated with the observed 40% decrease in ADC from the fifth
fraction to the eighth treatment fraction.
Conclusions: This pilot study demonstrated that longitudinal diffusion MRI is feasible us-
ing the 0.35 T ViewRay MRI. Larger patient cohort studies are warranted to correlate
the longitudinal diffusion measurements to patient outcomes. Such an approach may enable
response-guided adaptive radiotherapy. C 2016 American Association of Physicists in Medicine.
[http://dx.doi.org/10.1118/1.4942381]

Key words: MRI-guided radiotherapy, diffusion MRI, ADC, treatment response, adaptive therapy

1. INTRODUCTION Despite its potential, diffusion MRI-based adaptive radio-

Diffusion magnetic resonance imaging (MRI) is a promising
imaging technique for prediction of tumor response to radia-
tion therapy,1,2 earlier than traditional tumor size/morphology-
based response signatures.3 Baseline apparent diffusion coef-
ficient (ADC) or changes in ADC values between baseline
and post-therapy time points have been shown to correlate
with tumor control and patient outcome after radiotherapy.47
Therefore, diffusion MRI-based early response assessment
holds great promises for adaptive radiotherapy, wherein
the treatment plan would be altered during therapy based
on individual patients response. Such an adaptive therapy
strategy may support dose escalation for radioresistant tumors
or tumor subregions to improve locoregional tumor control,
or to de-escalate dose for well responding tumor subregions,
reducing surrounding critical structure toxicity.8
therapy has not been adopted. This is because, at least in
part, the optimal image timing has not been developed. In
some diffusion MRI studies for radiation therapy, diffusion
imaging was performed once before therapy, and another
time at weeks to months after therapy.5,9 In several studies,
diffusion MRI was also performed early during the course
of radiotherapy.6,7,10 The results of these studies point to
promising role of diffusion MRI for predicting tumor response.
However, these approaches may not adequately characterize
the temporal changes in diffusion. For example, a single
diffusion imaging during therapy could be too late for early
responders or too early for late responders. Furthermore, a
single diffusion measurement is sensitive to measurement
errors and noise at a single time point.
Because the optimal timing of diffusion MRI acquisition
has not been determined, we have elected to acquire the

1369 Med. Phys. 43 (3), March 2016 0094-2405/2016/43(3)/1369/5/$30.00 2016 Am. Assoc. Phys. Med. 1369
1370 Yang et al.: Longitudinal diffusion MRI using an MRI-guided radiotherapy system
diffusion image data at relatively high frequency, e.g., every
35 fractions. Recently, a real-time MRI-guided radiotherapy
system combining a 0.35 T MRI system and three cobalt
60 heads (MRIdian System, ViewRay, Cleveland, OH,
USA) has become commercially available. The novel sys-
tem combines real-time MRI-based tumor motion tracking
with radiation therapy capability in a single gantry.11 We
hypothesize that such a hybrid MRI-radiotherapy system may
eliminate many of the practical and scientific challenges and
bring diffusion MRI-guided adaptive radiation therapy closer
to widespread clinical utility. In this work, we report our early
experience of diffusion MRI at the ViewRay 0.35 T low field
MRI system and demonstrate its feasibility in longitudinal
tumor response assessment in a small cohort of patients
undergoing radiotherapy.
2. METHODS
We implemented a spin echo (SE)-based diffusion sequence
on the ViewRay 0.35 T MRI system using a single-shot echo
planar imaging (EPI) k-space sampling scheme, a commonly
used strategy at higher field strengths,12,13 with a maximum
gradient amplitude of 18 mT/m and a maximum gradient slew
rate of 200 mT/(m/ms). As a comparison, the state-of-the-
art higher field systems typically have a maximum gradient
amplitude of 4080 mT/m and a maximum gradient slew rate
of at least 200 mT/(m/ms). A whole-body radiofrequency (RF)
coil was used for transmission and a flexible surface coil was
used to receive the MRI signal. The same sequence was used
for both phantom and in vivo studies.
2.A. Phantom study
The SE-EPI sequence was used to acquire single-slice
diffusion images with b-values of 0500 with 100 mm2/s
increments using a commercially available diffusion phantom
(Model 128, High Precision Devices, Inc., Boulder, CO),
which contained 13 vials filled with aqueous solutions of
polyvinylpyrrolidone of increasing concentrations. The ADC
values of the vials were calculated using a standard exponential
fit of the mean signal intensity for each vial relative to the b
values. The calculated ADC values were compared with the
reference ADC values provided by the phantom manufacturer
using a commercial 3 T system.
2.B. In vivo study
Under an Institutional Review Board approved protocol, a
total of six patients were recruited in this study, including
three head and neck cancer and three sarcoma patients.
Individual written informed consents were obtained prior to
the MRI study. While all of the patients underwent the imaging
protocol, they were not all treated using the ViewRay system;
the three head and neck patient and one sarcoma patient were
treated using the ViewRay system and two sarcoma patients
were treated using Truebeam (Varian Medical Systems,
Inc, Corona, CA, USA) and Tomotherapy (Accuray,
Sunnyvale, CA, USA), respectively. All patients underwent
Medical Physics, Vol. 43, No. 3, March 2016
1370
conventionally fractionated IMRT. For patients who were
treated on the ViewRay system, imaging was performed
immediately after the treatment while the patient was in the
treatment position on the ViewRay patient couch. For patients
undergoing therapy on the other systems, the patient was
brought to the ViewRay system and imaged immediately
following his/her treatment. The treatment position was
reproduced on the ViewRay, aligning to the positioning lasers.
The diffusion images were acquired every 25 fractions
throughout the treatment during free breathing. For each
imaging session, ten slices were acquired interleaved with the
different b-values covering the gross tumor volume (GTV),
which was typically positioned near the isocenter. The pulse
sequence parameters included: flip angle = 90, echo time (TE)
= 160 ms, repetition time (TR) = 2600 ms, slice thickness
= 6 mm, EPI factor = 128, field of view (FOV) = 350350 mm,
b-values = 0, 100, 200, 300, 400, 500 mm2/s, 5 averages
and total scan time of 70 s for all ten slices. The diffusion
images were processed to obtain the ADC maps for each slice
using standard exponential fitting for each voxel. The b = 100
images were excluded from our exponential fitting to reduce
microvascular perfusion effects.14 Regions of interest (ROIs)
were drawn in the tumor on the diffusion images based on each
patients clinical GTV contours. A separate reference ROI was
drawn in the brain stem for the three head and neck cancer
patients. The ADC values for these reference ROIs were not
expected to change over the course of the treatment and were
used to assess the reproducibility of our ADC measurements.
3. RESULTS
3.A. Phantom study
The differences between our ADC measurements at 0.35 T
and the reference ADC values measured on 3 T were less than
5% across the ADC range of 0.41.1 103 mm2/s. These
phantom results confirmed that SE-EPI diffusion sequence on
ViewRay provided accurate ADC measurements.
3.B. In vivo study
Each patient successfully underwent 47 diffusion MRI
scans depending on their treatment length. Figure 1 shows
ADC maps from a 45 yr old patient (Patient #1) with squamous
cell carcinoma at the left maxillary sinus acquired at seven time
points during the course of treatment. The brainstem ADC
values remained stable throughout the treatment with a mean
brainstem ADC between 0.47103 and 0.57103 mm2/s for
all seven time points, which confirmed the ADC measurement
reproducibility. The mean ADC for the tumor increased from
1.3 103 mm2/s at the fourth fraction to 1.6 103 mm2/s
at the 31st fraction. In another head and neck cancer patient
(Patient #2) shown in Fig. 2, the brainstem ADC values also
remained relatively stable throughout the treatment (between
0.49103 and 0.56103 mm2/s); however, the tumor ADC
value substantially decreased from 1.5 103 mm2/s at the
second fraction of the treatment to 1.0 103 mm2/s at the
29th fraction (33% reduction).
1371 Yang et al.: Longitudinal diffusion MRI using an MRI-guided radiotherapy system 1371

F. 1. Longitudinal diffusion data from a 45 yr old head and neck cancer patient (Patient #1). The error bars indicate standard deviations within the ROI. The
brain stem ADC values did not significantly change over the course of the treatment with a nonsignificant linear fit slope of 0.002 103 mm2/s per day, which
is expected. For this patient, the average tumor ADC increased consistently over time from 1.3 103 to 1.6 103 mm2/s.

We hypothesize that for large tumors, our ADC maps may
be used to assess localized treatment response for tumor
subregions. Figure 3 shows a sarcoma patient (Patient #4)
with a 32 22 14 cm3 tumor. The simulation CT image
[Fig. 3(a)] did not differentiate well between tumor and
surrounding normal tissue. The diffusion-weighted image
[Fig. 3(b), b = 500] clearly shows the hyperintense tumor
that matched well with the patients GTV contour, which
was drawn by a clinical radiation oncologist based on the
simulation CT. In the corresponding ADC map [Fig. 3(c)],
there was considerable heterogeneity within the tumor with a
mean ADC of 1.34 103 mm2/s and a standard deviation of
0.41 103 mm2/s within the GTV contour. The ADC values
within the right lateral region of the tumor had much higher
ADC values than other regions.
In another patient (Patient #5) with pleomorphic liposar-
coma in the right forearm who underwent eight fractions
of radiotherapy on the ViewRay system, we acquired four
diffusion images at the time of MR simulation and at the
second, fifth, and eighth fractions. The ADC values dropped
from 1.56 103 to 1.12 103 mm2/s during the course
of treatment (1.56 103, 1.48 103, 1.45 103, and 1.12
103 mm2/s at MR simulation and at the second, fifth, and
eighth fractions, respectively). The patient underwent biopsy
47 days after radiation therapy, which showed a necrosis
score of less than 10%, an indication of poor response to
the treatment. The patients diagnostic MRI one month after
radiation therapy also indicated tumor progression with an
increase in size from 5.1 3.1 14.8 to 6.2 4.8 13.9 cm3.
4. DISCUSSION
In this work, we demonstrate for the first time the
preliminary feasibility of a longitudinal diffusion MRI strategy
at 0.35 T for patients undergoing fractionated radiotherapy
using an integrated MRI-radiotherapy system. In addition to
demonstrating the feasibility of low field diffusion imaging, to
our knowledge, this was the first study reporting diffusion MRI
data acquired every 25 fractions throughout the entire course
of radiotherapy. Although previous studies demonstrated ADC
changes at 13 weeks into the therapy and 38 weeks after
therapy for responding tumors,57,9,10 the imaging frequency
did not allow a systematic study to determine the nonlinear
temporal response and optimal timing for the treatment
response prediction due to coarse temporal sampling. Fur-
thermore, the temporal response of individual patients may
be highly variable and sampling the diffusion at finer time

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1372 Yang et al.: Longitudinal diffusion MRI using an MRI-guided radiotherapy system 1372

F. 2. Longitudinal diffusion data of a 51 yr old head and neck cancer patient (Patient #2). The error bars indicate standard deviations within the ROI. The
average tumor ADC was relatively constant (1.5 103 mm2/s) during the first three weeks of radiotherapy, and decreased to 1 103 mm2/s from week 4 until
the end of treatment. The ADC of the brainstem was relatively constant throughout the treatment with a nonsignificant linear fit slope of 0.001 103 mm2/s
per day.

intervals may facilitate individualized adaptive therapy. Based
on our preliminary experiences in six patients, the proposed
longitudinal diffusion MRI demonstrated different patterns of
temporal variations and intratumoral spatial heterogeneities
in ADC values. A larger patient cohort and follow-up study
is clearly warranted to correlate our longitudinal diffusion
imaging findings with patient outcome data. Nevertheless, our
longitudinal diffusion MRI strategy, once validated in a larger
cohort of patients, may represent a new paradigm of diffusion
MRI guidance for adaptive radiotherapy, wherein the diffusion
imaging is performed while the patient is on the treatment
couch in the same position as therapy.
The magnetic field strength of the ViewRay system is
0.35 T to minimize the electron return effect and maximize
spatial imaging accuracy.15 Low field strength typically results
in lower signal-to-noise ratio (SNR) efficiency; however, the
T1 relaxation rates of tissues typically decrease with field
strength, partially canceling SNR loss, and the diffusion
EPI readouts may potentially benefit from low field due to
the reduced absolute off-resonance frequencies. Our low-
field ADC measurements agreed well with values in the
literature that were acquired at higher field strengths.10 The
conventional MRI exams are typically performed on a stand-
alone diagnostic MRI system with 1.5 T or higher field

F. 3. (a) Simulation CT for a sarcoma patient (Patient #4) who underwent radiotherapy using the ViewRay system. The simulation CT shows good delineation
of bony structures, but did not differentiate tumor from the surrounding normal tissue. (b) Diffusion weighted image of the patient with b = 500 mm2/s where
the tumor is hyperintense and is clearly differentiated from the surrounding tissue. (c) The ADC map of the same patient demonstrating great heterogeneity of
ADC values within the tumor.

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1373 Yang et al.: Longitudinal diffusion MRI using an MRI-guided radiotherapy system
strength.2,16,17 Due to the fact that imaging and therapy are
on separate systems that are often operated by different
clinical departments, it is impractical to perform longitudinal
diffusion imaging during radiation therapy due to challenges
in scheduling and logistics. In addition, the images need
to be coregistered to the treatment simulation MRI or CT
images, a step that introduces additional errors. MRI-guided
radiotherapy systems, including the ViewRay system and other
systems that are currently under development,18 eliminate
the aforementioned challenges and may enable longitudinal
diffusion MRI in clinical workflow of radiotherapy.
a)Author to whom correspondence should be addressed. Electronic mail:
yyang@mednet.ucla.edu
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