2009 • Volume 1, Number 3
In this issue:
Quantitative Imaging Speaks Volumes about Biomarker
By P. DAVID MOZLEY, MD, and
ANDREW J. BUCKLER, MS
ANALYSIS TOOLS AND
Assessment of Tumors: Challenges and Opportunities
By EDWARD F. JACKSON, PhD
RSNA 2009: Quantitative Imaging/Imaging
BIOMARKERS IN THE LITERATURE
Search on Imaging and Treatment Response in Oncology
IN MY OPINION
Speaks Volumes about Biomarker Response
By P. DAVID MOZLEY, MD, and ANDREW J. BUCKLER,
Because all stakeholders are seeking
the most sensitive biomarkers for response, quantitative imaging is almost
completely aligned with the needs of both biopharmaceutical companies and
For a patient in an ordinary medical
setting, beginning a new therapy is analogous to starting a personal clinical
trial. Patients want to know as soon as possible whether a new treatment is
working, and if not, they want to search for alternatives as soon as possible.
Although informed patients understand that almost no treatment is without risks,
they don't want to endure those risks longer than necessary if the therapy is not
working. Bottom line: No one wants to waste time, effort, and money on
Biopharmaceutical enterprises view
clinical trials of products in much the same way. Like patients, those companies
want their products to alleviate suffering, succeed, and produce a return on
investment. Sensitive biomarkers for response allow industry to reduce the number
of patients required to test new products as well as decrease the time patients
remain in the study. The net effect would increase the number of new treatments
for unmet medical needs.
Although quantification is routinely used in medical
imaging to make critical decisions about a number of major health problems, it
has often been rather rudimentary in oncology. This is ironic, because
innovations in instrumentation and signal processing have long made it possible
to visualize large portions of many whole-body tumors with exquisite
Consider the case below. The
original Response Evaluation Criteria in Solid Tumors (RECIST) analysis suggested
that the patient remain in a prolonged state of stable disease; consequently, the
subject added little of the analytical power needed to distinguish between the
two arms of the trial. In retrospect, volumetric image analysis suggests that
this patient had an initial response to treatment but could have switched
therapies several months before changes in unidimensional line lengths met
criteria for progressive disease. All stakeholders lose when there is a delay in
diagnosing progressive disease.
CT scans were
acquired every 6 weeks in a patient with lung cancer enrolled in a trial of a
novel drug or placebo plus the standard of care. RECIST line lengths were placed
by radiologists working for a central laboratory. Tumor volumes were measured by
another image analysis laboratory.
â€¢ Baseline: The CT scan acquired immediately before starting a
new treatment regimen
â€¢ SLD: Sum of longest diameters placed on a single slice of a
tumor according to the RECIST formalism
â€¢ Tumor volume: The whole volume of the corresponding
â€¢ Dashed lines represent categorical response
In the top panel, all values are
normalized for the measurements at baseline immediately prior to the initiation
of treatment. RECIST suggests the patient remained in a state of stable disease
for the duration of the trial.
In the bottom panel, all values are
normalized for the smallest measurement that preceded the time point, referred to
as the "prior nadir." All negative values reflect a decrease in size, while all
positive values represent an increase in size. An increase in 20% from the prior
nadir is categorized as progressive disease. This patient showed clinical signs
of progression before the longest diameters ever reached RECIST threshold values
for progressive disease. In contrast, volumetric image analysis revealed clear
signs of progression more than 5 months before the patient came off the
QIBA Advances Quantitative
Imaging in Oncology
QIBA is one of the few places where imaging device manufacturers, software
developers, academicians, officers in regulatory agencies, representatives of
biopharmaceutical enterprises, and other stakeholders can collaborate to create
strategies for advancing quantitative imaging in oncology.
The QIBA Volumetric CT Technical
Committee has now produced a systematic research program to determine whether
volumetric image analysis is practical, reproducible, and valuable to all of the
stakeholders. So far, results have been extremely encouraging. Delivering more
sensitive biomarkers for responses to treatments for cancer will be a win-win for
P. David Mozley,
MD, is a senior director of clinical research for Merck Research Laboratories and
represents the Extended PhRMA Imaging Group on the QIBA Quantitative CT
Committee. Andrew J. Buckler, MS, is an imaging analytics specialist who has
worked in the medical device manufacturing sector for more than 20 years. Dr.
Mozley and Mr. Buckler co-chair the QIBA Quantitative CT Committee along with Dr.
ANALYSIS TOOLS & TECHNIQUES
Assessment of Tumors: Challenges and Opportunities
F. JACKSON, PhD
One key advantage of MR is the wide
range of intrinsic tissue properties that can be assessed by the appropriate
choice of parameters defining the associated measurement technique.
In neuroimaging applications, for
example, routine MR imaging provides a qualitative means of assessing the
breakdown of the blood brain barrier as reflected by the extent of gadolinium
contrast agent extravasation (T1-weighted sequences), the extent of vasogenic
edema (T2-weighted and T2-weighted fluid attenuated inversion recovery
sequences), the presence of blood products such as hemosiderin, methemoglobin
(T1-weighted and T2* susceptibility-weighted images), and the ability to assess
brain atrophy and regional white/gray matter abnormalities (using proton
density-weighted and/or magnetization prepared gradient-echo
Neurovascular anatomy can be
evaluated with or without the injection of exogenous contrast agents (using
time-of-flight and/or phase-contrast MR angiography techniques). Such
wide-ranging contrast mechanisms and acquisition techniques have frequently led
to MR as the modality of choice for soft tissue neuroimaging. Recent improvements
in acquisition rates and contrast agent-enhanced MR angiographic techniques have
expanded such applications throughout the body.
Use of Functional MR
In addition to such morphological, qualitative assessments, there is increasing
interest in MR-based assessments of the functional status of tissue.
A partial, but not comprehensive,
list of such functional MR measures includes those used to detect changes in
cellular volume/density due to disease process or response to therapy as
reflected by the degree of restriction of water diffusion (diffusion-weighted MR
imaging); changes in the microvascular environment (microvascular volume, flow,
and permeability assessment using dynamic contrast-enhanced and/or dynamic
susceptibility change MR imaging); and biochemical changes (in vivo MR
Such functional measures are now
being used as secondary or exploratory endpoints in several Phase I/II clinical
trials of targeted therapies or combinations of such therapies with conventional
treatment regimens [1-3].
However, to fully realize the power
of such a broad range of anatomical and functional techniques and to use them in
a quantitative manner in clinical trialsâ€”and ultimately in
clinical patient managementâ€”several challenges must be
1) Characterization of the sources
of bias and variance and mitigation of such effects at the instrument,
acquisition protocol, and data analysis levels.
2) Standardization, or at least harmonization, of signal response for a given
protocol across instruments from a single vendor and, ultimately, across
instruments from multiple vendors.
3) Standardization of acquisition and processing protocols used to obtain
quantitative anatomical and/or functional measures.
4) Validation of such quantitative measures using accepted outcome-based
Various groups are now addressing
each of these areas.
â€¢ QIBA Quantitative MRI
Committeeâ€”issues pertaining to areas
â€¢ National Cancer Institute (NCI)
Cancer Imaging Program Reference Image Database to Evaluate Response MR
Subcommitteeâ€”areas 1 and 2.
â€¢ International Society for
Magnetic Resonance in Medicine (ISMRM) Ad Hoc Committee on Standards for
Quantitative MR (with the National Institute of Standards and
Technology)â€”developing a system phantom that can be used to
address areas 1 and 2.
â€¢ American Association of
Physicists in Medicine (AAPM) Quantitative Imaging Initiative MR-related task
and working groupsâ€”areas 1 and 2.
Protocols in Clinical Trialsâ€”area 3, acquisition
â€¢ NCI-funded Imaging Response Assessment Teams and Quantitative
Imaging Networkâ€”areas 1â€“4.
Finally, the RSNA Imaging Biomarker Roundtable,
comprising representatives from these and other groups, seeks to harmonize and
enhance each of these efforts. The RSNA Toward Quantitative Imaging (TQI)
initiative, which offered education exhibits at RSNA 2009, aims to educate
radiologists and other physicians about the challenges and potential rewards of
many to mention by nameâ€”are also involved in many of these
efforts or are poised to become involved.
There are many challenges facing
MR-based quantitative imaging biomarkersâ€”some of them
considerable. However, given the broad range of anatomical and functional
information potentially available in a quantitative fashion using such
techniques, the potential rewards are clearly sufficient to continue and,
hopefully, accelerate our efforts to address such challenges.
Dynamic Contrast-Enhanced Magnetic Resonance Imaging as an Imaging Biomarker. J
Clin Oncol 2006 July; 24:3293-98. Hylton N.
Quantitative Imaging Biomarkers in the Clinical Development of Targeted
Therapeutics: Current and Future Perspectives. Lancet Oncol 2008 August;
9:766-76. O'Connor J.P., et al.
Diffusion-Weighted Magnetic Resonance Imaging as a Cancer Biomarker: Consensus
and Recommendations. Neoplasia 2009 February; 11:102-25. Padhani A.R., et
Edward F. Jackson,
PhD, is section chief for MR and ultrasound physics and professor and deputy
chair of the Department of Imaging Physics at the University of Texas M.D.
Anderson Cancer Center in Houston. He is co-chair of the QIBA Quantitative MR
Committee, a member of the RSNA TQI Steering Committee, chair of the ISMRM Ad Hoc
Committee on Standards for Quantitative MR, and chair of the AAPM Working Group
on Standards for Quantitative MR Measures.
RSNA 2009: Quantitative
Quantitative imaging and imaging
biomarkers were well represented at RSNA 2009.
At an open informational meeting
held November 30, RSNA Science Advisor Daniel C. Sullivan, MD, offered an
overview of imaging biomarkers and the QIBA process. The meeting marked the 2
year anniversary of an RSNA 2007 meeting of quantitative imaging
Since then, the Quantitative Imaging
Biomarkers Allianceâ€”comprising representatives from the
pharmaceutical industry, imaging equipment manufacturers, imaging informatics
companies, government agencies, imaging societies, the clinical community and
RSNA leadershipâ€”has progressed from discussion to action. The
QIBA Committees and the Uniform Protocols for Imaging in Clinical Trials (UPICT)
subgroup of the CTSA Imaging Working Group reported on the past year's
The QIBA Committees noted their
experimental groundwork with phantoms and human data as well as the development
of documentation in the form of QIBA Profiles. The UPICT subgroup has developed a
template for a uniform imaging protocol and is engaged in extracting and
reviewing proffered protocols into the UPICT template.
Lakeside Learning Center at
On the exhibit floor at the RSNA annual meeting, the
QIBA Committees and UPICT presented educational posters and held Meet the Expert
sessions and question/answer segments throughout the week.
The Toward Quantitative Imaging:
Reading Room of the Future area focused on quantitative imaging and
analysis. An educational showcase offered visual and experiential exposure to
quantitative imaging and biomarkers through 15 exhibitor products integrating
quantitative analysis into the image interpretation process. The Reading Room
of the Future also featured hands-on exhibits and informational posters,
computer-based demonstrations, and Meet the Expert presentations throughout the
In his December 1 Annual Oration in
Diagnostic Radiology (see Daily
Bulletin article), Dr Sullivan emphasized the importance of extracting
quantitative information from scans and noted that quantification is attainable
with current imaging modalities. He also highlighted the work of RSNA initiatives
such as QIBA, the Imaging
Biomarkers Roundtable and Toward Quantitative Imaging that
aid the transition toward quantitative imaging.
QI/IMAGING BIOMARKERS IN THE
PubMed Search on Imaging
and Treatment Response in Oncology
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