**Project to Develop an Imaging Archive to Facilitate Cancer Change
Analysis Tool Development**

**Purpose:**

We will collect a number of imaging studies evaluating the response of
cancer to treatment, starting with CT and PET/CT, from a variety of
sites across the country, meeting technical specifications, and having
defined clinical outcomes, as outlined in this document. It is our hope
that these studies can be analyzed by multiple researchers at academic
institutions and software development companies, as well as others who
want to test their metrics or tools on high quality images with proven
clinical outcomes. The cases will allow the above individuals to test
both the reproducibility of their analysis schemes as well as how
predictive their metrics or tools are of patient clinical outcome. It is
a major goal in the creation of this archive to expedite the widespread
use of the best radiology metrics and tools, both qualitative and
quantitative, to allow for optimal imaging of the change in cancers in
response to new and emerging therapies.

**Nature of the Effort to Assemble the Archive of Cases**:

The creation of the archive is anticipated to involve a close
collaboration between oncologists, radiologists, and informatics
experts. Many trials have been completed, are ongoing, or are planned
across the nation, with a large variety of anti-neoplastic drugs,
radiation treatment methods, or devices. A central feature of these
trials is the use of imaging, largely CT, but to a lesser degree PET/CT,
and MRI. Due to tremendous recent upgrades in technology the majority of
these imaging evaluations are performed with advanced CT, PET/CT, or
MRI, many with extremely thin reconstructed slices permitting
exceptional reformatted images and volumetric displays. These studies
are frequently timed to therapy and are used to assess patient response,
particularly in the determination of time to progression of their
tumors. RECIST is the most widely used metric of tumor response, based
on change in the size of neoplastic lesions, and CT is the most commonly
used modality.

A major goal of this project is to link well defined clinical outcome
data, available from the myriad number of trials, both past and present,
with scans of sufficiently high quality to facilitate analysis of how
imaging predicts patient clinical response to treatment. We will need to
link patient imaging examinations to other patient metadata on the
archive including patient demographics, other serious medical ailments,
nature of their treatment, tumor histology, and clinical outcomes in
response to therapy. Cases are anticipated to be drawn from trials
utilizing imaging carried out by national cooperative groups,
pharmaceutical companies, the national cancer institute, individual
reputable sites, and collaborating combinations of these entities.

Major issues which need to be addressed early on are patient
confidentiality, the identification of partners in the clinical and
commericial area willing to contribute cases, and the informatics issues
of transferring large imaging data sets and the required links to other
patient metadata. Efforts are ongoing in the current CaBIG collaboration
to address storing images on the the NCIA, linking imaging information
to other patient metadata, and addressing patient confidentiality in the
sharing of this information. The archive we plan to develop will start
with small series of cases from existing trials and can be expanded as
the tools developed through CaBIG maturation.

**Inclusion and Exclusion Criteria for Cases on the Archive:**

These will be as flexible as possible to allow for the rapid accrual of
cases.

Inclusion Criteria:

Technical (Initially for CT but subsequently to be expanded to other
modalities):

1.  slice thickness of 5 mm or less, ideally 2.5 mm or less

2.  adequate opacification of the major blood vessels, including the
    aorta and pulmonary arteries in the chest; the aorta, inferior vena
    cava, portal vein (and major branches), mesenteric vessels, for
    abdominal examinations.

3.  Continuous coverage with no skip areas. For the chest would be from
    the thoracic inlet through the lung bases. For abdominal/pelvic CT
    would be from just above the dome of the liver or left hemidiaphram
    (whichever is higher) through either the top of the iliac crests or
    lower pole of the most caudal kidney (whichever is lower) or the
    pelvic floor (if scan is to include pelvis).

4.  Ideally single breath hold for the chest and for the abdomen/pelvis

5.  Scanner should be multidetector, not single slice (4 detectors or
    more)

Case Mix:

1.  The two types of cancer, which have unfortunately fairly short and
    dismal clinical outcomes, and are leading sources of case material
    are advanced lung and colorectal carcinoma. Initially we will focus
    on collecting patients with these malignancies at an advanced stage,
    with staging baseline and follow-up CT examinations meeting our
    inclusion criteria. These patients will be considered by existing
    criteria as non-resectable at the time of the first scan contributed
    to the archive, although may have had prior surgery for their tumor.

2.  We will collect cases from trials having both lung and colorectal
    cancer at various stages at baseline and follow-up examinations,
    with both difficult and easy to discern lesions and their associated
    degree of change on follow-up evaluation.

3.  One or two radiologists will score each collection of cases received
    in terms of the ease of detection of metastatic lesions. Each
    patient series of scans will be given a score of 1-3, with 3=high ,
    2=moderate, and 1=low degree of difficulty in making this
    assessment. The average of the individual patient scan series scores
    will be calculated to yield an overall score for the collection. The
    same approach will be taken to give a degree of difficulty in
    assessing the change of neoplastic lesions over time between scans.
    The scans will be scored based on how difficult overall it is for
    the radiologists to assess the change in size of metastases with
    factors including the complexity of the shape of the mass or masses
    (ie., boundaries, contiguous spread into neighboring structures),
    and degree of change between scans used in making this assessment.

4.  Cases will be required to have at least 4 consecutive scans over
    time (a baseline prior to therapy with at least 3 follow-up
    studies), with the intervals between scans clearly defined.

Patient Information:

Required:

1.  demographics including age, and gender.

2.  performance status

3.  type of therapy (specific drug, radiation method, device) and timing
    of the therapy relative to the time of the baseline and follow-up
    scans.

4.  type of malignancy (histologically confirmed) and stage

5.  Documented outcome measures including time to progression of cancer
    (usually determined currently by CT with the time to progression
    interval being the time from baseline CT to first CT with documented
    progressive disease using RECIST criteria), disease specific
    mortality or overall survival. Cause of death has to be documented.

Desired, but not required:

1.  Smoking history

2.  family malignancy history

3.  genomic information

4.  biologic activity or other markers of patient malignancy (including
    serologic measures) and times acquired.

5.  quality of life surveys and times performed

Exclusion Criteria:

> Technical (for CT):

1.  Motion or other artifacts compromising the images to preclude use of
    3-D software tools

2.  slice thickness \>5 mm

3.  suboptimal IV contrast bolus. Non-contrast studies of sufficient
    quality can be included but will be indicated as such

4.  area of coverage does not include the whole chest for chest CT or
    area of interest in abdomen or pelvis to evaluate the extent of the
    metastases for colorectal carcinoma

5.  scan technology below current state of the art (ie single slice
    scanner) or variation between scans for individual patient is too
    large to permit adequate change analysis of the metastases (ie PE
    protocol following a conventional timing chest CT to assess tumor
    change).

Case Mix:

1.  Currently only patients with advanced lung and colorectal carcinoma
    will be included. No other tumor types will be collected.

2.  Cases having less than 4 scans over time.

Patient Information:

1.  Patient time to progression of cancer and both disease specific
    mortality and overall survival missing

2.  Type of tumor not provided or provided without histologic
    confirmation

3.  Patient treatment and timing of treatment is not provided.

4.  No patient demographics (age and gender)

5.  Patient has other life threatening malignancy beside colorectal or
    lung cancer. Patient can have either colorectal or lung cancer (not
    both active). Basal cell and non-metastatic squamous cell skin
    cancers do not preclude inclusion. Successfully treated prior life
    threatening malignancies do not preclude inclusion if the patient
    has been disease free for over five years.

6.  patient performance status (ie severe heart disease or other
    debilitating illness) may result in death during follow-up period
    from cause other than underlying lung or colorectal carcinoma.

**Work Plan:**

Short Term:

4-6 months:

Acquisition of at least 3 CT collections of cases meeting above
inclusion and exclusion criteria. One collection is already being
annotated from Roswell.

Begin testing with multireader project comparing at least several sites
making RECIST measurements on up to 3 marker lesions per scan, as well
as using other to be defined metrics. Solicited sites will include IRAT
centers as well as other interested non-IRAT centers. I have a contact
at Strong Memorial Hospital in Rochester NY who has expressed an
interest in becoming involved both as a source of patients (ie advanced
lung cancer) and as an independent radiologist reader.

Readings of the test sets can be compared among multiple diverse
readers, including radiologists with differing degrees of experience,
and physician extenders (physician assistants, nurse practitioners,
technologists).

Software developers can also compare their tools in lesion change
analysis on these same collections and compare with 1)human observers
using traditional metrics (RECIST), 2) qualitative metrics, and 3)
software tools in combination with human interaction, to determine the
most reproducible metrics between readers and the metrics which are most
predictive of patient outcome.

Any number of pilot projects comparing radiology metrics, with different
types of readers and quantitative software tools, and combinations
thereof can be initiated at this early stage. A mechanism must be
developed to contribute the observer reads and quantitative analysis
tool output to a behind the scenes database to allow an objective
scientific comparison of the different radiology parameters for cancer
change analysis.

The NCIA will likely be source for the different CT collections. The
informatics dealing with image transfer, patient de-identification, and
tools to allow searching the collections by relevant parameters should
be developed in the early phase.

Individuals will have to be identified to develop an appropriate case
mix based on the type of malignancy, the magnitude of the tumor change
over time, the visibility and complexity of the lesions in the
collection. These individuals will also be responsible for maintaining
the integrity of the archive in terms of the quality of the images and
the associated patient metadata.

The mechanism to allow seemless transfer of case collections to the
archive, and retrieval of case collections by interested parties will
have to be developed.

Intermediate:

6 months-2 years

Additional CT collections of cases meeting the above inclusion and
exclusion criteria, as well as others to be developed, will be added.

Other modalities will be added to the archive, using the above developed
model as a framework within which to achieve this. PET/CT and MRI are
the likely candidates but other modalities in the development stage can
be added as well.

The CaBIG effort can be engaged to facilitate the image transfer to and
from the archive, links to other patient data, and search capabilities.
It is anticipated this will become more feasible as the CaBIG effort
matures.

Additional studies can be performed comparing traditional, and new
developing radiology metrics on cases being entered into the archive
predominantly from completed trials. The archive could also be used to
house ongoing collections of imaging studies with associated metadata.
Robust previously validated and newly developed radiology metrics could
be tested on these imaging sets to allow for ongoing feedback. The most
reproducible, predictive metrics will be promoted in the imaging
community and the worst performing ones will have their use discouraged
with the determination made through ongoing research of how the metrics
perform on cases on the archive. The database on which the imaging
information resides will be perfected during this phase. The CaBIG
software packages may facilitate this effort.

Long Term:

Consideration of a business model where a commercial entity would
facilitate contribution of trial cases to the archive, collect imaging
evaluation data for pharmaceutical companies or other companies involved
in treating cancer. Standardized, reproducible reports of tumor
response, based on established imaging metrics could be prepared by such
a company for the FDA or others in the scientific community. A teaching
file could also be developed to train radiology residents or others
involved in reading cancer imaging studies. Software tools could be
developed by the company to facilitate on line searches of relevant
cancer cases with similar features to those being evaluated in active
clinical practice. A help menu providing guidelines and relevant
vocabulary could be provided to end users? This has to be flushed out
quite a bit more.