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Quality-of-Life End Points in Oncology Drug Trials

Quality-of-Life End Points in Oncology Drug Trials

ABSTRACT: Health-related quality of life (HRQL) is a multidimensional construct that represents the patient’s perspective on valued aspects of health and functioning. Over the last several years, the pharmaceutical industry, as well as health care providers and the patient advocacy community, have shown increasing interest in HRQL as an outcome measure. Pharmaceutical companies and other sponsors of cancer clinical trials are seeking novel approaches with which to establish the benefits of treatment and to differentiate their products from other marketed products. Health care providers hope to provide cancer patients with therapies that positively affect their quality of life. To date, however, most oncology drug approvals have been based on traditional end points, such as survival and tumor response rate. This article will focus on some of the lessons learned from recent reviews of HRQL data and will describe some of the many challenges that lie ahead. ONCOLOGY 13(10):1439-1442, 1999]

Introduction

With a small number of exceptions, notably in
the treatment of refractory tumors, oncologic drugs are marketed on
the basis of a demonstrated clinical benefit, such as survival.
Health-related quality of life (HRQL) is a multidimensional construct
that represents the patient’s perspective on valued aspects of
health and functioning.[1,2] For oncologic drugs that cannot be shown
to have an impact on patient survival, demonstration of a favorable
effect on HRQL outcomes could be considered evidence of clinical
benefit.[3,4] Randomized, controlled clinical trials are the
preferred venue for assessing HRQL outcomes in oncology.

Issues Related to Study Conduct and Design

Measurement of HRQL is accomplished through the use of scales or
instruments that solicit patients’ responses to questions
related to their physical, psychological, and social functioning.
Other dimensions of HRQL, such as cognitive or sexual function, may
also be evaluated, and there may be global assessments of health or
life satisfaction. Measures directed at tumor-related symptoms are
preferable to measures of “larger” psychosocial
consequences, as the former are likely to be more sensitive.

Choosing an Appropriate HRQL Instrument

A spectrum of HRQL instruments has been developed for the evaluation
of cancer patients. These range from general questionnaires to
disease- or treatment-specific measurement scales to ad hoc
instruments that are specific to a single study.[5] To balance the
trade-offs inherent in the various types of instruments, many
oncology experts have proposed using a battery of several HRQL
instruments in a clinical trial. For example, a cancer-specific core
instrument that measures aspects common to many cancers, such as the
general Functional Assessment of Cancer Therapy Scale (FACT-G), may
be combined with one or more modules that measure concerns specific
to a certain kind of cancer or anticancer treatment, as
appropriate.[6]

Although the use of batteries of instruments provides maximal
flexibility, this practice can make cross-study comparisons
problematic if instruments or modules are not used consistently
across various trials. In addition, the multiplicity of outcomes may
make it difficult to draw statistical inferences.

It is therefore important for investigators to identify, in a
prospective manner, the specific HRQL outcomes that will be assessed
as evidence of drug effectiveness, the measurement times that will be
considered critical, and the minimal differences in HRQL scores that
will be considered clinically meaningful. In some cases, an
exploratory effort may be needed to construct specific plans for
definitive studies. It is very important to address the issue of
whether the instrument is measuring benefit, toxicity, or both.

Minimizing Bias

Every attempt should be undertaken to minimize bias in the conduct of
trials that assess HRQL outcomes. Double-blinding is the preferred
approach for minimizing bias, and it can be carried out successfully
in studies involving oral agents. The Breast Cancer Prevention Trial
(P-1) conducted by the National Surgical Adjuvant Breast and Bowel
Project, for example, successfully randomized over 13,000
participants to tamoxifen (Nolvadex) or placebo in double-blind
fashion.[7] If double blinding is not feasible, it may nonetheless be
possible for study personnel who perform HRQL assessments to be
blinded to patients’ treatment assignments and their responses
to treatment.

Procedures for the conduct of interviews or patient completion of
questionnaires should be standardized across interviewers, patients,
and clinical sites. Study personnel should be carefully trained to
ensure data quality. Ideally, HRQL outcomes should be measured prior
to patients’ discussions with their health care providers
regarding treatment response, adverse events, or other concerns that
could affect their evaluation of HRQL. Clearly, knowledge of
one’s treatment assignment could introduce bias, resulting in
expressions of disappointment about having received the standard
therapy on the one hand, or heightened expectations about receiving
the newer, experimental therapy on the other.

Case in Point: Importance of Pilot-Testing Novel Treatment
Concepts

Uncontrolled studies offer researchers the opportunity to gain
experience with the use of HRQL instruments prior to large-scale
implementation in a randomized, controlled trial. The following
example illustrates the importance of testing novel treatment
concepts in a pilot trial.

Historically, it has been difficult to demonstrate the benefits of
cytotoxic chemotherapy in patients with hormone-refractory prostate
cancer using traditional end points, such as objective tumor response
or survival. Tumor response evaluation has been particularly
problematic for the osteoblastic bone disease that commonly occurs in
these patients.[8]

A small, uncontrolled study examined the palliative response to
treatment with mitoxantrone (Novantrone) plus prednisone, as measured
by changes in pain scores and analgesic scores (the latter derived
from data entered in patients’ medication diaries).[8] These symptomatic
patients with hormone-refractory prostate cancer experienced a
measurable palliative response despite a disappointing objective
tumor response to therapy.

The performance of this study allowed critical design issues related
to patient selection, choice of pain scales, and pain response
definitions to be refined prior to the initiation of a larger
randomized trial. Logistical concerns involving patient compliance
with serial pain assessments and completion of analgesic diaries were
also addressed. In addition, the safety of the treatment regimen in
this elderly patient population with comorbid illnesses was assessed.

A confirmatory randomized trial then compared mitoxantrone plus
prednisone vs prednisone alone and served as the basis for marketing
approval of mitoxantrone for the treatment of pain related to
hormone-refractory prostate cancer.[9] Like its predecessor, the
randomized trial also evaluated the relief of pain in symptomatic
patients, with palliative response defined as a 2-point reduction in
pain intensity on a 6-point scale, associated with stable analgesic
use and lasting a minimum of 6 weeks. The pain intensity scale was
derived from the McGill-Melzack Pain Questionnaire.[10,11]

Combination treatment produced a superior palliative response rate
and superior median duration of palliative response with an
acceptable safety profile. Median time to progression (defined on the
basis of progression of pain, analgesic use, or radiographic end
points) was also prolonged in the patients treated with mitoxantrone
plus prednisone. Median survival was similar in both arms—not an
unexpected finding in this patient population.

Although this trial was not blinded, members of the FDA’s
Oncologic Drugs Advisory Committee agreed that a 2-point improvement
in pain intensity measured on a 6-point scale was clinically
meaningful in this patient population.[12] Furthermore, the magnitude
of the effects of the mitoxantrone-prednisone arm on response
duration and time to progression could not be readily attributable to
patients’ knowledge of their treatment assignment or
investigator bias.

Thus, the advisory committee concluded that the trial was an
adequate, well-controlled study that provided convincing evidence of
net clinical benefit for the combination of mitoxantrone plus
prednisone over prednisone alone in patients with hormone-refractory
prostate cancer. In 1996, the FDA granted marketing approval for
mitoxantrone in combination with corticosteroids as initial
chemotherapy for patients with pain related to advanced
hormone-refractory prostate cancer.[13]

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