2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

What Metrics Should Be Used to Define Clinical Benefit
in Sarcomas? Is There Consensus Internationally?
The concept of “clinical benefit” appears—on the surface—as
intuitively clear and simple: that which helps a
patient feel, function, or survive better. The challenge is that
measuring anything other than survival is impossibly complex
and very insensitive to variations that may be highly
relevant and desirable to patients. Even “survival” is a
complex and composite measure dependent on many variables;
as such, survival does not directly measure a single
intervention such as an individual new drug or therapy. One
could keep a patient alive longer than the patient might
wish, for example, using heroic measures that do not provide
a desirable or reasonable quality of life; alternatively, some
patients who lose hope might withdraw and avoid potentially
life-prolonging standard therapy options. The challenge
for physicians caring for patients as well as for
physicians serving as regulators (or advisors to regulatory
bodies) is to focus on the needs of the patients in a given
clinical context.
This critically important element of clinical context is
often glossed over or ignored entirely in discussions of
clinical benefit. The fact that people with different types of
illnesses and with different risks of morbidity or mortality
may choose to make different decisions represents one clear
and compelling piece of evidence that clinical context truly
matters. The risk of life-altering symptoms, such as pain or
severe dyspnea from massive lesions pressing on nerves or
major bronchi, is a major concern to many patients with
advanced sarcomas, given the fact that sarcomas can occur
in young, otherwise healthy individuals and can grow to
KEY POINTS
● It is impossible to generate statistical proof of beneficial
activity in every rare disease for every possible
therapy.
● Physicians must learn to read between the lines and
make clinical decisions on the basis of best available
evidence and incomplete information.
● All drugs have side effects and risks, but professional
judgment can and must be used in discussions with
patients about management options once standard
“proven” therapy has failed.
● Clinical context is very important for weighing risks
and benefits, and patient preferences must also be
integrated into such clinical context for decision making.
● Best supportive care may sometimes be the most
appropriate option for patients with incurable diseases
and with no available therapy of proven value,
but such decisions also should take into account other
lines of evidence as well as patient preferences.
● Assessments of cost-effectiveness require clinical expert
opinions, and clinical experts have an important
role in advocacy for patient preferences and patient
needs, as well as rigorously interpreting limited data
by conventional methods of statistical proof.
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SLEIJFER, JUDSON, AND DEMETRI
significant bulk before interfering with function in these
patients. However, once that tipping point has been reached,
the patients may have a limited ability to move from
“adequate function” to “decreased function with symptoms”
to “severe dysfunctional status” or even death. This contextual
distance is highly relevant for patients with STS, who
risk living with the burden of very bulky disease, often far
more bulky than patients with other cancers.
This is directly applicable to a controversy that is perhaps
one of the most contentious in clinical oncology research
today: what is the value to patients of maintaining patients
in a progression-free state? This is particularly vexing in
rare-disease research, where it may be difficult or impossible
to prove any effect on overall survival (OS). This is
exemplified by two large phase III clinical trials that enrolled
patients with a variety of STS subtypes in different
clinical settings. PALETTE was a phase III international
trial in which a limited spectrum of patients with STS
were randomly selected to receive either placebo or a multikinase
inhibitor, pazopanib, in the setting of metastatic
disease that was progressing despite prior standard chemotherapy.
1 In contrast, SUCCEED was a phase III international
trial in which patients with a broader array of
sarcomas were randomly selected to receive either placebo
or a mammalian target of rapamycin inhibitor, ridaforolimus,
in the setting of metastatic disease that was stable or
in objective remission (partial or complete) following previous
standard chemotherapy. 2 These trials both met statistically
predefined endpoints that demonstrated the beneficial
effects of the two drugs under study (pazopanib or ridaforolimus,
respectively) compared with placebo. However,
neither study was able to prove a statistically significant
effect of either drug on OS. Nonetheless, these trials highlight
the challenge: in patients with metastatic sarcomas,
what is the metric of clinical benefit? Is this metric constant
across clinical settings? In both studies, patients with metastatic,
incurable sarcomas were enrolled and studied. However,
in PALETTE, these patients had progressive disease
that had already progressed despite prior standard systemic
therapy; in SUCCEED, these patients entered the trial with
evidence of disease control from prior standard therapy.
These differences in clinical context may or may not be
important in weighing the clinical benefit of a new treatment,
especially in the palliative setting such as metastatic
sarcomas.
The relative risks and benefits of any new treatment are
clearly important, but the relative risks of uncontrolled
progressive sarcoma are also important to keep in mind.
This is especially true in diseases such as sarcomas that
tend to strike a somewhat younger and overall healthier
population than many cancers. Finally, the lack of tools to
dissect out subtle variations and differences in patient
preferences as well as patient experiences with disease and
with treatments also complicates the problems of assessing
clinical benefit in this field.
The rarity of sarcomas only adds to the complexities of
interpreting such data and making clinical extrapolations to
interpret true clinical benefit for patients. Ultimately, clinical
experience, expert judgment, and the totality of available
evidence must be used to assess the clinical benefits to
patients with advanced sarcomas.