2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

IMAGING BIOMARKERS IN RENAL CANCER
istration (FDA) approval for several drugs, has never been
demonstrated to be a surrogate endpoint for survival in this
disease. One of the few studies in which this progression
metric was formally evaluated (which has been reported in
abstract form only) demonstrated that there is a correlation
between progression-free survival and overall survival in
renal cancer but that the Kendall’s tau statistic was 0.50,
which is considered a modest correlation and not sufficient
for general use as a surrogate endpoint. 4
A number of new immune therapy regimens being developed
might have activity in renal cancer as well. An important
issue to consider with regard to therapeutic monitoring
of response to these drugs is that tumor shrinkage and
inhibition of tumor growth might be delayed, presumably
while the immune function is activated. As such, one needs
to allow for a period of growth before declaring such an agent
ineffective. Whether the criteria suggested for melanoma in
the context of ipilimumab therapy will apply in renal cancer
as well remains to be determined. 5
Use of Tumor Size Measurements as a
Continuous Variable
Traditional tumor burden measurements using either
bi-dimensional or uni-dimensional criteria, and which were
derived from reliability measurements, categorized changes
in tumor size into variables labeled “complete response,”
“partial response,” “stable disease,” and “progressive disease.”
The questionable clinical relevance of these categories
has already been noted. Just as importantly, categorization
of an otherwise continuous variable leads to loss of statistical
information. Using actual RECIST-based measurements
rather than their aforementioned categorization, one can
compare two groups (e.g., a treated and an untreated group)
with use of standard statistical approaches for group comparisons.
Because RECIST measurements are not normally
distributed, an initial transformation of the data (typically
log-transformed) and formal rules for how to manage missing
measurements and difficult-to-measure lesions need to
be constructed. We undertook this exercise, and our simulations
suggest that differences between an experimental
and a control group in terms of changes in tumor size can be
KEY POINTS
● RECIST-based metrics of response, stable disease,
and progression are arbitrary.
● In the context of the vascular endothelial growth
factor pathway and mammalian target of rapamycindirected
therapy in renal cancer, the correlation
between RECIST-based disease progression and survival
is modest.
● Volumetric tumor measurements, dynamic contrastenhanced
imaging quantitative parameters, and
functional imaging with radionuclides have all been
proposed as novel predictive and intermediate biomarkers
for renal cancer therapy.
● Standard cross-sectional imaging and clinical judgment
remain the best pragmatic approach to therapeutic
monitoring in renal cancer.
reliably detected with a sample of approximately 150 patients.
6
Although a detectable difference between an experimental
and a control group using tumor size measurements as a
continuous variable could be reliably ascribed to the intervention
with use of standard statistical tests, such a difference
clearly does not demonstrate that the difference has
clinical relevance. Thus, a continuous tumor size metric
could theoretically be used as a phase II clinical trial
endpoint but not a phase III trial endpoint without additional
data elucidating the relationship between changes
in tumor size and clinically relevant endpoints. To this end,
we have conducted additional simulations on data from
phase III renal cancer trials of sorafenib and pazopanib and
suggest that such an approach, if used in a phase II trial,
would be highly predictive for the phase III results. 7 Obviously,
further work assessing the relationship between tumor
burden and clinical outcome is necessary.
Novel Approaches to Tumor Burden Assessments
Challenges with analysis and interpretation of unidimensional
and bi-dimensional measurements of tumor
size have led some authors to contend that volumetric
measurements would be more predictive of clinical outcome.
This belief is based on the observation that many tumors,
including metastatic renal cancer, do not always grow or
shrink in a spherical fashion. This observation raises the
hypothesis that the poor correlation between measurements
of tumor burden and clinically relevant outcomes such as
survival are due to the fact that the uni-dimensional and
bi-dimensional measurements do not accurately reflect tumor
burden. Just as important, the manual extraction of
tumor burden data is cumbersome and, thus, the RECIST
guidelines exclude many lesions. More recently, a number of
algorithms have been developed to more accurately determine
tumor volume from standard cross-sectional images. 8
It is now becoming technically possible to address this
underlying hypothesis, and several studies are attempting
to do so.
Contrast-Enhanced Imaging
With the advent of therapies directed at the VEGF pathway
in renal cancer, it became quickly apparent that
contrast-enhanced imaging provides additional information
beyond tumor size alone. A number of investigators realized
that these targeted agents lead to a hypoperfused appearance
of lesions, consistent with the mechanism of action of
the agents. It has thus been proposed that more formal
measurements of this hypoperfusion could not only be a
measure of drug effect (a pharmacodynamic endpoint) but
also an indication of clinical benefit (an intermediate or
surrogate endpoint). A number of criteria for assessing these
changes has been used, of which the most common are the
“Choi Criteria,” which classify a “response” as tumor shrinkage
of at least 10% or a decrease in tumor density of at least
15%. 9 Some studies have suggested a correlation of “Choi
Response” to VEGF pathway inhibitors with clinical outcome
in patients with renal cancer. 10 A major challenge with
these criteria, however, is that computerized tomography
(CT) scans are not always well standardized with regard
to the timing of image acquisition in relation to contrast
administration or in the contrast administration rate, which
are both critical variables in determining the degree of
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