2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

enhancement seen. Furthermore, the criteria are categoric
in nature, raising the same issues as discussed earlier for
categorization of tumor size metrics.
Investigators have thus attempted to conduct a more
formal analysis of uptake, distribution, and washout of
contrast agent in lesions using pharmacokinetic approaches.
Although this can be done with both contrast-enhanced CT
and magnetic resonance imaging (MRI), the requirement for
multiple images and associated radiation exposure, as well
as the limited resolution traditionally associated with CT
scans, has led to MRI being used in most of these studies. A
number of quantitative variables describing uptake, distribution,
and washout of contrast agent can be derived, with
K trans , a complex variable dependent on both tumor blood
flow and perfusion, being the most commonly used variable.
Studies in patients with renal cancer have demonstrated
that VEGF pathway inhibitors decrease K trans in a reliably
detectable manner, but that there is little to no correlation
between this decrease and clinical outcome. 11,12 Some have
suggested that baseline K trans might be predictive of outcome
in the context of these therapies, but that hypothesis
remains to be proven. 11,12
MRI-based measurements also have a number of additional
limitations, including imaging time required to obtain
the parameters, difficulty in determining these quantitative
parameters in more than one or a few lesions, heterogeneity
in the quantitative parameter even within one
tumor, (which is technically challenging to measure), and
the nonlinear relationship between contrast enhancement
and contrast concentration, which is required for assessing
K trans and other parameters.
Alternative approaches using blood flow determined by
nuclear medicine techniques and molecular probes are being
developed, but the technology is currently immature, and
correlations with clinical outcome remains incompletely
determined.
Technetium Bone Scans
Bone scans have been used extensively in oncology imaging
to determine the presence of metastases in bone. Given
the limitations of standard CT-based cross-sectional imaging
in x-ray dense bone and the ability to image the entire
skeleton with a bone scan, a bone scan has been a valuable
modality for clinical decision making. Nevertheless, it needs
to be remembered that technetium is taken up at sites of
bone remodeling and thus the bone scan detects bone remodeling
not the tumor per se. Other pathologic conditions,
including inflammation, Paget’s disease, and fractures, can
all lead to increased bone remodeling and positive bone
scans. Furthermore, in renal cancer, sensitivity of bone
scintigraphy has been reported to be 62%. 13 Lastly, dramatic
antitumor effects might actually lead to an increase in
bone modeling and a worse-appearing bone scan. This has
been most prominently demonstrated in prostate cancer
(see article in the ASCO 2012 Educational Book by Biting
and Armstrong). Given these limitations, bone scans are a
poor modality for monitoring response to therapy in renal
cancer.
FDG-PET
The Warburg effect is one of the most ubiquitous and
earliest recognized features of malignancy. In this phenomenon,
malignant cells preferentially utilize an aerobic glyco-
286
lysis pathway, which in turn leads to dramatic upregulation
of glucose transport. Fluorodeoxyglucose is a nonmetabolizable
radioactive glucose analog that is taken up in cells by
these same glucose transporters. It is therefore a useful
imaging diagnostic marker for many cancers. Interestingly,
renal cancers, and especially clear cell renal cancers, do not
uniformly have elevated glucose uptake; in fact the sensitivity
of FDG-PET for small pulmonary nodules that were
subsequently histologically demonstrated to be metastatic
renal cancer is 64%. 14
The mTOR inhibitors are known to lead to hyperglycemia
in part because of a more general inhibition of glucose
uptake, and glucose uptake has been proposed to be a
pharmacodynamic biomarker for mTOR therapy. Perhaps
more interesting and related to the variable glucose uptake
in renal cancer specifically, it has been proposed that renal
cancers that have elevated glucose uptake would be preferentially
sensitive to mTOR inhibition. 15 We tested this
concept in a small single-arm trial and demonstrated that
treatment with everolimus reliably leads to a decrease in
FDG uptake, and is thus a pharmacodynamic biomarker.
However, baseline FDG measurements did not correlate
with patient outcome, and the correlation between the
degree of decrease in FDG uptake and patient outcome was
quite modest as well. 16
Summary and Clinical Implications
WALTER M. STADLER
Many of the discussions here are more directly applicable
to the use of imaging and imaging biomarkers in clinical
trial monitoring. Although their findings may not be directly
applicable to the clinical care scenario, the studies conducted
to date provide some guidance. Most importantly,
these studies have strongly suggested that more sophisticated
imaging methods such as FDG-PET or quantitative
parameters derived from measurements of contrast uptake
and washout are unlikely to be useful for monitoring response
to treatment directed at the VEGF pathway or
mTOR or in selecting specific therapies. In addition, bone
scans, although useful from a diagnostic perspective, have
rather limited utility in therapeutic monitoring as well.
Thus, for clinical monitoring of response to therapies directed
at VEGF and mTOR in renal cancer, we are left
essentially with standard cross-sectional imaging.
Because agents directed at the VEGF pathway and mTOR
lead to tumor shrinkage that does not always meet standard
RECIST criteria, or lead only to tumor growth inhibition,
“lack of growth” is typically used as a clinical indicator of
benefit. The obvious clinical challenge is that renal cancer
can be indolent, and it is often impossible to determine
whether any observed lack of growth is because of or despite
of the administered agent. Conversely, growth exceeding
the standard 20% above nadir used for determining progressive
disease in clinical trials might still reflect a certain
degree of growth inhibition by the agent. Clinical management
therefore requires an understanding of the patient’s
history, clinical disease symptoms, and clinical toxicities,
and a thorough review of the images themselves. Careful
clinical judgment is required to provide the patient with the
maximum treatment duration of an agent from which he or
she is benefiting, but no longer. Such judgment may become
even more challenging if immune-stimulating agents, from
which delayed responses may occur, become clinically available.