Achieving the Best of Both Worlds

Although measuring quality of life (QoL) may not always have been viewed as a well-established end point in clinical trial design, increasing recognition of its importance and the availability of more validated and reliable tools have led to its incorporation as an outcome measure in many modern-day studies. More than half of the phase III trials that have been sponsored by the National Cancer Institute (NCI) in the four most common cancer types (breast, colon, prostate, and lung) during the last decade have included patient-reported QoL end points. Moreover, most oncologists acknowledge the value of gathering and analyzing such data even in routine clinical practice, although in a busy practice setting with limited time and resources, such tasks may be difficult and time consuming to accomplish. Although the subject of QoL is routinely discussed with patients and their families, we may wrongly assume that we share a common definition of QoL among ourselves and with our patients. Gotay et al suggested the following definition of QoL back in 1992: “a state of well-being [that includes] two components: (1) the ability to perform everyday activities which reflect physical, psychological, and social well-being and (2) patient satisfaction with levels of functioning and the control of disease and/or treatment-related symptoms.” The NCI Web site defines QoL more generally as “the overall enjoyment of life,” presumably leaving the details to providers and patients to individualize how that is manifest in the context of an incurable disease such as advanced pancreatic cancer. Even today’s best available therapies produce a 1-year survival rate of less than 50% in this disease, making the maintenance or improvement of QoL during that remaining time critically important. This importance was recognized 15 years ago in the pivotal study that led to the approval of gemcitabine for this same disease indication, given that it was the first cancer clinical trial to use clinical benefit response (CBR) as the primary end point. As defined in that original study, CBR represented a composite of measurements of pain, Karnofsky performance status (PS), and weight— all direct reflections of patient QoL. Since that time, we have come a long way in measuring the benefits and risks of treatment as they affect the lives of patients. It is time to take the lessons from this history and apply them when we review new studies. In the article that accompanies this editorial, Gourgou-Bourgade et al report the results of a companion study to the PRODIGE (Partenariat de Recherche en Oncologie Digestive) 4/ACCORD (Actions Concertees dans les Cancers Colo-Rectaux et Digestifs) 11 trial in patients with metastatic pancreatic cancer, in which serial measurements of QoL were obtained. This phase III trial garnered considerable attention when it was first reported in 2010 because it established oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as a new first-line standard for patients with advanced pancreatic cancer, at least for those with a robust PS. When compared with gemcitabine, the previous standard, this multidrug regimen produced improvements in overall survival and other clinical outcome measures that were not only statistically significant but also clinically meaningful. In a disease in which practice-changing clinical advances have been few and far between for the last several decades, these findings were hailed as a major breakthrough. The ongoing reluctance of some oncologists to offer FOLFIRINOX, however, may be in part a result of understandable concerns regarding the potential negative impact this treatment could have on patients’ QoL. The regimen has been shown to be associated with substantial toxicity, including fatigue, GI symptoms, and sensory neuropathy. Questions that inevitably arise for any patient faced with treatment decisions, particularly in the setting of an incurable illness, include: What are the relative risks and benefits of the proposed therapy? How much QoL will be sacrificed for a chance at improved survival? The QoL data presented by Gourgou-Bourgade et al provide reassurance that across multiple measures, FOLFIRINOX preserves and improves QoL to a greater degree than standard gemcitabine monotherapy. During study participation, patients were asked every 2 weeks to complete the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire, a well-validated 30-item questionnaire that incorporates functional and symptom scales as well as a patient’s global health status/QoL. Although patients on both chemotherapy arms showed an improvement over time with respect to specific symptoms (including pain and anorexia), only those receiving FOLFIRINOX did better from a perspective of their overall (global) health status. Equally important, the time until definitive deterioration (defined as a decline of 10 or 20 points on a given measureoftheQLQ-C30scale)wassignificantlylongerinpatientstreated with FOLFIRINOX for a number of different symptoms, functional domains, and global health status. In other words, any additional toxicities that are associated with the more aggressive chemotherapy regimen seem to be mitigated by more effective control of a patient’s cancer-related symptoms for a longer duration of time. Unfortunately, this analysis, like so many before it, is limited by a missing data problem caused by systematic exclusion of patients who became ill over time during the study (and who therefore may have had difficulty completing the QoL questionnaire) and by protocoldriven exclusion of patients who stopped therapy. As a result of these JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 1 JANUARY 1 2013