Whereas previous studies have shown that both symptom ratings and responses to quality-of-life questionnaires are associated with survival, especially for patients who have cancer with a shorter prognosis, this study is among the first to examine whether measurement of baseline symptoms or symptom change in an individual patient with advanced cancer might assist in estimating the prognosis for that patient.
Results of this study support our hypothesis that moderate to severe baseline symptoms and worsening symptom burden during the first cycle of chemotherapy are strong independent predictors of overall survival in patients with advanced NSCLC who were eligible to receive chemotherapy. Of the multiple symptoms rated by patients, moderate to severe coughing (rated as 4 or greater on the MDASI’s 11-point scale) at baseline had the most significant independent predictive value for poor survival in this patient population, especially for patients with poor performance status (PS = 2). Additionally, we found that fatigue, shortness of breath, or poor appetite that had increased in severity by 1 or more points on the MDASI from baseline to the end of the first chemotherapy cycle were independent predictors of poorer overall survival in these patients.
Translational and clinical research has set the stage for personalizing chemotherapy in the management of NSCLC to improve response to treatment and survival of patients with NSCLC.23
Some molecular biomarkers are promising as to their prognostic value for tumor response and survival in patients with advanced NSCLC.23–25
Ultimately, however, the clinical application of these biomarkers may rely on the feasibility and ease of testing them in clinical practice. In contrast, symptom assessment via patient report can provide a simple, readily available, yet robust prediction of the patient’s near-term survival, especially when more elaborate tests are not available in daily oncology practice. Further investigation into the additional prognostic value of symptom measures along with biomarkers for advanced NSCLC is merited.
Previous research on patient-reported outcomes has examined both health-related quality-of-life and symptom information as predictors of survival. For example, Eton and colleagues6
reported that changes in quality-of-life component scores over 2 cycles of chemotherapy were predictive of clinical outcomes in a group of patients with advanced lung cancer. Our study adds to these findings by suggesting that an individual patient’s symptom scores—particularly when scores exceed specified cut points—have utility in predicting outcomes, at least for patients with advanced disease. Such cut points are often used in the clinic to control symptoms. On the basis of widely accepted symptom-control guidelines,18,19
we provisionally set 4 or greater on a 0–10 scale to describe a moderate to severe symptom and its association with survival outcomes. The potential utility of such a categorization on severity scales has been well investigated for pain management in individual patients,26
and it has been explored for categorizing the severity of other symptoms as well.17,27,28
Our results support for measuring a few highly relevant symptoms as a simple, robust tool for predicting outcomes in a busy clinic setting. Repeated symptom ratings can be collected reasonably quickly: patients typically complete the MDASI in 5 minutes or less. In the current study, we took advantage of the MDASI’s multisymptom approach and its simple 0–10 rating scale to compare a large number of symptoms. Fatigue, shortness of breath, and pain were the most severe symptoms by the end of the first chemotherapy cycle (), identical to findings from a retrospective study of the prevalence and intensity of lung cancer symptoms near the time of death.7
This study not only confirmed the prognostic value of the component scores, but also identified the specific symptoms that were most relevant to overall survival status. In fact, the examination of model fitting () demonstrated the better prognostic value of specific symptoms compared with component scores. Our results have added evidence that a single-symptom score is responsive to changes over time and is unambiguous as to which specific symptom is changing, and to what degree.29
Investigating the interaction between symptom severity and baseline performance status as a predictor of survival is justified by the considerable number of patients (approximately 30%) with advanced NSCLC who had poor performance status (PS = 2) in this study. Although these patients typically are qualified for chemotherapy, they can expect only a small survival benefit.30
Even with a small sample size, the study clearly demonstrated that the risk for death in patients with moderate to severe coughing and poor performance status at baseline was 20.6 times higher than for patients with only mild coughing and good performance status (PS = 0–1) (P
< .0001), a strong indicator of which patients would be most likely to die before the end of a chemotherapy clinical trial. This model could potentially provide a practical tool for clinical use, as it may more precisely predict overall survival than either symptom severity alone or PS alone.
This study was limited in that it was conducted in a single institution and with a mostly white non-Hispanic patient sample; the impact of race or ethnicity on survival is thus inconclusive. The multivariate analyses that excluded the minority patients showed a diluted impact from PS on overall survival and demonstrated an increased role for symptom report as an independent predictor. This result warrants further study in a sample containing sufficient minority patients to confirm the role of race/ethnicity in PRO-predicted survival. Also, although previous reports indicate that pain is an important prognostic factor in lung cancer, it was not a significant predictor of overall survival in the current study.12
Improvements in the standard care for pain management in oncology practice in many cancer treatment centers in recent years may have diluted the potential prognostic impact of pain in this study.
As with any other potential marker for survival or progression, recommendations about patient care cannot be made without repeated cross-validation studies of the prognostic value of symptom-report models in other cohorts of patients with advanced NSCLC being treated in medical oncology clinics. Cross validation in a much larger multi-institutional study would greatly enhance any recommendations about the use of symptom reports as predictors of outcome. Nonetheless, the results obtained from this relatively small patient sample were statistically significant, with at least 90% power to detect a hazard ratio of 2.5 or higher for baseline moderate to severe symptoms at an alpha level of .05. This level of power strongly supports the effect and clinical relevance of the results and thus the use of symptom reports in predicting outcomes in advanced NSCLC.
The stability of symptom report based on a single baseline time point needs to be established. Even so, the potential predictive power of symptom report in individual patients, as found in this study, is noteworthy and can easily be examined in other databases via the methods we report here. The increasing use of symptom measures at baseline and longitudinally in observational studies and clinical trails could provide data to further evaluate the observations reported here. Symptom assessment by MDASI takes less than five minutes, and MDASI symptom data can be obtained remotely via electronic (computer or telephone-computer systems) that cause little patient burden. The use of symptom report as a predictor is also supported by the evident clinical and biologic significance of increasing symptom severity as a marker of disease severity.
In conclusion, this study highlights the importance of validated symptom-burden assessment tools, such as the MDASI, in gaining patient-report information that, beyond facilitating better symptom control in oncology care, is useful for predicting overall survival in patients with advanced cancer. Such symptom-based prognostic information, taken together with physician-rated PS, may help clinicians gain a sense of the expected near-term survival for individual patients with advanced NSCLC who qualify for chemotherapy.