2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

NONSTANDARD THERAPIES FOR ADVANCED SARCOMAS AND GISTS
Preparing a Professional Organization Statement
First, it is valuable to work closely with patient advocacy
groups in order to understand the needs and concerns of the
patients themselves. A carefully argued case in favor of a
new treatment will be enhanced by the input of patients in
the process of preparing the scientific and clinical case. It
may even be appropriate on occasion to submit a joint report.
You need to be aware of who you represent as a clinical
expert and ensure that you have consulted widely before
submission. This also lends the submission more weight.
You are required to state that you are an expert in the
treatment of patients who have the condition for which
NICE is considering the new treatment, that you understand
the scientific and clinical basis for the treatment, and
that you are an employee of an organization representing
clinicians who treat the condition in question. The framework
for the submission takes into account a number of
specific issues that include the current therapy for the
disease; any important variations in treatment, including
the merits of alternative treatment, if any; whether there
are any patient subgroups that might benefit particularly;
how the treatment would be used; and the existence of any
guidelines for the disease in question.
You will need to explain the scientific basis for the treatment,
especially the number and quality of clinical trials
and how they might relate to everyday practice. Particular
emphasis might be placed on side effects and toxicities, that
is, the balance between benefit in terms of disease control
and the potentially adverse effects of treatment on quality of
life.
In practice this means having an in-depth knowledge of
the disease and its treatment, being familiar with the
clinical trial evidence for the new treatment, and in particular
being able to argue effectively that the clinical benefit
outweighs the common adverse side effects.
What Are the Key Issues?
Cost-effectiveness in cancer treatment is determined by
the cost per quality adjusted life year (QALY) gained. The
calculations take into account the total number of patients
treated relative to the number who might live longer. Hence
if the percentage of patients who benefit is small and the cost
is high, a drug could be deemed not to be cost-effective even
if the benefit is prolonged for the few for whom it works. For
example, in Technology Assessment T209 on high-dose imatinib,
it is stated that the estimated median increase in life
expectancy for imatinib 800 mg compared with best supportive
care (which included imatinib 400 mg) was 4.2 months,
but cost-effectiveness for high-dose imatinib was not demonstrated
compared with sunitinib. 12 This was despite the
fact that no comparison of sunitinib with imatinib 800 mg
has been performed. In addition, in this particular assessment,
no data on the benefit of imatinib 800 mg in patients
with KIT exon 9 mutant GISTs were regarded as permissible
for evaluation because the assessment focused exclusively
on patients whose cancers had progressed on imatinib
400 mg. The data on the PFS for patients with KIT exon 9
came from randomized studies (62005 and S0033), in which
patients received either 400 mg or 800 mg imatinib from day
1. These data were of course evaluated in a meta-analysis
demonstrating a significant benefit in terms of PFS for 800
mg for the exon 9 mutant group (p � 0.012), 13 but because
they did not address the limited scope of this appraisal they
were not considered.
Quality adjustment is often contentious, largely because
there are few data available and the tools to assess it are
somewhat crude. Essentially, the assumption is that patients
with advanced cancer already have an impaired
quality of life and hence any prolongation of life is weighted
according to the disease itself and its likely effect on quality
of life and further weighted by the side effects of treatment.
In Technology Assessment 209, the “utility” of patients with
GISTs on best supportive care is given as 0.577, based on a
very small study. 12 In the technology assessment for trabectedin
in the treatment of advanced STS, the “utility”
values for progression-free and progressive disease health
states are stated as 0.653 and 0.473, respectively. 14
It must be said at this stage that utility in this context
means the mean quality of life of patients relative to 1.00
being perfect, at this stage of life, and hence a presumed
reduction in the perceived value of any extension of life. This
is an assumption that patients tend not to accept. However,
it must be acknowledged that we do need better data on the
effect of cancer on quality of life at different stages of disease
in order to help make such assessments more realistic and
meaningful.
Incremental Improvements and the Comparator Approach
In determining the value of a new therapy, the standard
approach is to compare the new treatment against the
current best available therapy and if there is no significant
improvement in PFS or OS, then it is deemed ineffective, or
if the improvement is small and it is expensive, then it is
deemed cost-ineffective. However, no system has yet been
devised to evaluate the cost-effectiveness of sequential effective
therapies, each with an individual small incremental
benefit but a significant combined effect. It is apparent that
survival of patients with many cancer types is increasing
because of earlier diagnosis, more effective primary treatment,
and more effective therapy for advanced disease.
What is less easy to quantify is the effects of new targeted
therapies on survival and whether sequential therapy with
effective agents, each with a limited duration of benefit, is
truly beneficial or not. The current methods used by regulators
and health care utility bodies such as NICE do not
address this issue.
The Question of Balance
There is no publicly funded health care system in the
world with unlimited resources, and methods need to be
developed that are transparent and respected to restrict
health care costs while ensuring value for money. No one
questions the value of imatinib for the treatment of GISTs or
chronic myeloid leukemia. However, a number of high-cost
new drugs have been licensed for the treatment of common
cancers, which have a statistically significant, but nevertheless
limited effect on PFS or OS, or indeed have yet to
demonstrate any effect on survival. Notwithstanding the
issue of cumulative incremental benefit, this needs to be
kept in mind when preparing evidence to funding bodies or
health care evaluation organizations such as NICE. In
addition, it is clearly easier to demonstrate statistically
significant differences in PFS or OS in common cancers,
where large trials can be performed, compared with rare
cancers, even if the benefits are greater.
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