It is now common for clinicians and patients to face choices among treatments that are highly similar in efficacy and even in prolonging survival. As a result, differences in treatment toxicity and in the patient’s status during the survival period have become critical variables in making treatment choices and in developing new therapies. Paramount in evaluating both toxicity and quality of survival time is the inclusion of patient-reported outcomes as important measures of treatment differences. These outcomes can take a variety of forms, including measures of the differences in symptom severity, perception of daily functioning, feelings of well-being, global impressions of the impact of treatment on daily life, satisfaction with treatment, and health-related quality of life (QOL).
Because these patient-outcome variables are becoming more important relative to "hard" end points such as survival or time to recurrence, decisions about which patient-outcome measures to use and how to interpret them for patients, health-care professionals, and policy makers will need to be made. Almost all of these outcome measures will ultimately depend on the patient’s perception of his or her status, before and after becoming ill and receiving treatment. The patient’s representation of this change forms the basis for making practical judgments about how treatment should progress.
As treatments that depend on such subjective outcomes emerge, how such treatments will be "valued" becomes a major issue. Will patients, given subjective outcome information about the treatments, opt to pursue them? Will physicians use this outcome information to recommend and prescribe treatments? When such treatments are being developed, will approval agencies decide they are beneficial? Will agencies (public and private health funders) decide that such treatments are worth paying for?
Thus, when a treatment offers little or no survival advantage, yet seems to improve how patients feel, judgments about the worth of the treatment will be made by several audiences who will ultimately determine whether the treatment is effective, should be approved, and will be used. Here we discuss the concept of symptom burden as a way to portray patient status, and offer a definition of symptom burden as an outcome measure.
We can trace the origin of the word "symptom" from the Greek "symptoma," which means "anything that has befallen one." A more useful definition, however, is provided by Webster, and states that symptom "is the subjective evidence of disease or physical disturbance observed by a patient." Implicit in this definition is the subjective and negative nature of symptoms. Symptoms are an observation by the patient; ie, the person experiencing the evidence of disease or physical disturbance. Symptoms can be the subjective expression of the disease itself, or the products of disease treatment, the latter often referred to as side effects or toxicities. Symptom burden can be thought of as the subjective counterpart of summary expressions of disease such as tumor burden.
Patients typically experience multiple concurrent symptoms, due either to the disease or its treatment. We propose that a measure of symptom burden be a summative indicator of
- The severity of the symptoms that are most associated with a disease or treatment
- A summary of the patient’s perception of the impact of these symptoms on daily living, including activity, mood, ability to work, and ability to relate to others.
Most clinical trials currently include one or more measures of quality of life. In 1996, the American Society of Clinical Oncology stated that quality of life was an end point secondary only to survival. The US Food and Drug Administration (FDA) recommended that quality of life is a more important measure of treatment efficacy than most other traditional end points for drugs that do not have an impact on survival.
Clearly, improving a patient’s quality of life is a goal of all medical treatment. Based on the World Health Organization definition of health, quality of life includes psychological and social functioning as well as physical functioning, and incorporates positive aspects of well-being as well as negative aspects of disease and infirmity. Among health researchers, a common consensus is that quality of life is a multidimensional construct composed of at least four dimensions:
- Physical function (ie, daily activities, self-care, etc)
- Psychological function (ie, emotional/mental status, mood)
- Social function (ie, social interactions, family dynamics), and
- Disease/treatment symptoms (ie, pain, nausea, fatigue).
The comprehensive nature of quality of life, however, is both one of its attractions and its difficulties as an outcome measure. Quality of life is best viewed as a subjective evaluation of life as a whole. In this section, we present the potential advantages of symptom-burden measure, highlighting its potential utility as a supplement to QOL measures.
Clinical Condition and Quality of Life
QOL measures may be relatively insensitive to obvious changes in clinical condition. As a multidimensional construct, a measure of quality of life may include aspects that go beyond the impact of cancer or its treatment. Among bone marrow transplant patients, studies have shown patients rating their quality of life as above average despite the persistence of significant physical and psychological symptoms. For example, Bush and colleagues conducted a descriptive study of quality of life, psychological distress, demands of long-term recovery, and health perceptions of 125 bone marrow transplant survivors. They were no different from individuals sampled from the general population with regard to their perceived current health and health outlook. However, 10 or more years posttransplantation, long-term survivors continued to experience a moderate incidence of lingering complications and demands, including emotional and sexual dysfunction, fatigue, eye problems, sleep disturbance, general pain, and cognitive dysfunction.
Molassiotis et al found that long-term autologous bone marrow transplant survivors rated their quality of life as good to excellent, although 20% reported symptoms of anxiety, 10% had signs of clinical depression, and 20% had not returned to full-time employment. McQuellon et al found that quality of life and mood improved slightly in patients following autologous bone marrow transplant, despite the fact that 30% had problems with sexuality, fatigue, and depressive symptoms.
These studies show that patients may report their quality of life as improved or unchanged, despite changes or deterioration in health. QOL measures in such situations are liable to yield discrepant results compared with the proposed symptom- burden measure. Further, results indicating that patients’ quality of life did not deteriorate may also imply that intervention need not be undertaken, possibly masking the issue of specific residual symptoms that require intervention.
Symptom burden is correlated with quality of life, and many QOL measures (eg, European Organization for Research and Treatment of Cancer [EORTC], Functional Assessment of Cancer Therapy [FACT]) have components that measure symptoms. Symptom severity is a strong predictor of scores on QOL measures suggesting the potential of symptom- burden measures as an immediate indicator of deteriorating quality of life. For example, Bull and colleagues studied quality of life among women with recurrent breast cancer. Results showed that self-reported physical symptoms were a strong predictor of postrecurrence ratings of overall quality of life. In a study of 206 adult patients with multiple myeloma, Poulos and colleagues looked at the relationship between pain and mood disturbance, and the factors that influence quality of life. They found that pain and mood disturbance scores were significant predictors of quality of life in this group of patients.
Symptom-burden measures may be more informative about true differences in patient status when comparing treatments. A randomized clinical trial compared the quality of life of patients treated with single-agent paclitaxel(Drug information on paclitaxel) vs doxorubicin(Drug information on doxorubicin) as first-line therapy for advanced breast cancer. Quality of life was measured using the EORTC Quality of Life Questionnaire (QLQ)-C30 and the Rotterdam Symptom Checklist. Results showed that no statistically significant differences were observed in either the functional scales or the global QOL scores during the third cycle of chemotherapy. However, cross-sectional analyses of data at the end of cycle 3 showed that patients in the doxorubicin arm had significantly more nausea/vomiting and loss of appetite than those in the paclitaxel arm. The authors concluded that there is a trend toward greater burden of disease and treatment and lower general health status associated with doxorubicin therapy.
When using QOL measures, components assessing symptom burden are more responsive indicators of changes in patient status. For example, a 1985 randomized phase III study compared patients with low-grade cerebral glioma who received high-dose (59.4 Gy in 6.5 weeks) vs low-dose (45 Gy in 5 weeks) radiotherapy with conventional techniques. A QOL questionnaire, consisting of 47 items that assessed a range of physical, social, psychological, and symptom domains, was included in the trial to measure the impact of treatment over time. No difference in survival was observed between the two treatment strategies.
The authors also report that, in general, the results suggest no major differences in quality of life between the two treatment arms. However, patients who received high-dose radiotherapy reported significantly more fatigue/malaise and insomnia immediately after radiotherapy, and poorer emotional functioning at 7 to 15 months postrandomization. For the remaining QOL domains, no statistically significant differences between the two treatment arms were found. The authors concluded that conventional radiation therapy for low-grade cerebral glioma using an administration schedule of 45 Gy over 5 weeks is at least as good as prolonged treatment in terms of clinical efficacy, survival, and quality of life.