Quality of life assessment using patient-reported outcome (PRO) measures: still a Cinderella outcome?

…the person who takes medicine must recover twice, once from the disease, and once from the medicine. William Osler (1849–1919) William Osler was one of the first physicians to articulate the harms not just the benefits of modern medicine and a century since his pithy observation, we have seen many exciting advances made in the treatment of cancer. Better understanding of molecular biology together with improved diagnostics, surgical and radiotherapy techniques and innovative, more targeted systemic therapies mean that more patients have a genuine prospect of cure or surviving longer with their disease. Nothing comes without cost, however, and the iatrogenic harms and burdens, both acute and long-term, associated with novel drug therapies, remain under-reported, under-estimated and consequently under-treated [1.Sivendran S. Latif A. McBride R.B. et al.Adverse event reporting in cancer clinical trial publications.J Clin Oncol. 2014; 32: 83-89Crossref PubMed Scopus (107) Google Scholar]. To enable wise decision-making before embarking on different therapeutic management strategies, patients and doctors need much more information than that usually available in publications of many clinical treatment trials. How one functions and feels during and after treatment are salient concerns yet primary outcomes of studies are invariably overall survival (OS) and more commonly in advanced disease, progression-free survival (PFS). The paper by Marandino et al. [2.Marandino L. La Salvia A. Sonetto C. et al.Deficiencies in health-related quality of life assessment and reporting: a systematic review of oncology randomized phase III trials published between 2012 and 2016.Ann Oncol. 2018; Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar] shows an alarming dearth of quality of life (QoL) end points in major clinical trials of novel therapies in the common solid tumors. The authors illustrate how even when patient assessments were included in the trials, the results were generally insufficiently reported, subject to significant publication delays long after those of the main trial and were often found in low impact journals. We have to do better in our evaluation of expensive novel products. The sometimes modest OS or more often PFS gains that excite clinical scientists and pharma share-holders may be of little value to patients experiencing some serious and burdensome side-effects. Conclusions stating that ‘patients found side-effects tolerable’ should be viewed with some skepticism as trials that are conducted for registration and licensing purposes rarely have lengthy enough follow-up to chart some of the problems that emerge later in the clinic [3.Seruga B. Templeton A.J. Badillo F.E. et al.Under-reporting of harm in clinical trials.Lancet Oncol. 2016; 17: e209-e219Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. There are many other reasons to be concerned about the quality of the traditional adverse event (AE) data derived from clinical trials. There is a lack of concordance between toxicity and symptom recording by patients using patient-reported outcomes (PROs) and the ‘gold-standard’ for establishing AEs namely the Common Terminology Criteria of Adverse Events (CTCAEs) graded by clinicians [4.Basch E. The missing voice of patients in drug-safety reporting.N Engl J Med. 2010; 362: 865-869Crossref PubMed Scopus (428) Google Scholar]. Worryingly although AE grades are regarded as objective many even experienced clinicians are unaware of the precise definitions for the different grades. Furthermore, studies show quite poor inter-rater reliability between clinicians asked to rate the same symptom [5.Atkinson T.M. Li Y. Coffey C.W. et al.Reliability of adverse symptom event reporting by clinicians.Qual Life Res. 2012; 21: 1159-1164Crossref PubMed Scopus (148) Google Scholar]. Unfortunately, there is little reason for complacency about some of the trial publications that do include QoL from PRO measures (PROMs). A myriad of deficiencies can be observed including inappropriate choice of PRO, inadequate descriptions as to how missing data were handled and naïve or biased statistical methods to name but a few. Just because a questionnaire purports to measure QoL, this does not necessarily mean that it is suitable for the patient population, their disease status or the treatments being trialed. Many commonly used generic PROMs such as the EORTC-QLQ-C30 [6.Aaronson N.K. Ahmedzai S. Bergman B. et al.The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.JNCI. 1993; 85: 365-376Crossref PubMed Scopus (10805) Google Scholar] and the FACT-G [7.Cella D.F. Tulsky D.S. Gray G. et al.The functional assessment of cancer therapy scale: development and validation of the general measure.JCO. 1999; 11: 570-579Crossref Scopus (4380) Google Scholar], are multi-dimensional with domains covering areas such as physical, functional, social, sexual and emotional well-being. Reporting merely the mean total scores from such measures can mask or dilute important effects, both positive and negative, that might exist at a domain level. Both the EORTC and FACT-G can be accompanied by disease-specific modules or subscales that contain important relevant items. The FACIT system has a whole suite of subscales that are treatment specific permitting better evaluation of symptoms associated with, e.g. monoclonal antibodies, TKIs, hormone therapies, taxanes and antiangiogenesis drugs [8.FACIT Functional Assessment of Chronic Illness Therapy; http://www.facit.org/ (16 October 2018, date last accessed).Google Scholar]. In oncology trials especially those conducted in tumor sites with a poor prognosis or in advanced disease, attrition is inevitable and a major challenge. If one treatment arm is significantly more effective than another, then missing data are unlikely to be missing at random and sophisticated statistical methods are required. At the very least it is vital that at an individual item, questionnaire or patient level, the reasons for missing data be that toxicity, progression or death, are available for scrutiny. CTCAE grades only offer information regarding the presence at any time of a symptom. Good PRO measures when analyzed appropriately, can provide a clearer description of the trajectory of important side-effects, when they start, if they ever improve or if they persist until end of treatment. Group mean scores are not very helpful for individual decision-making, so responder analyses showing what proportion of patients, in each treatment arm, at each time point, ever improve from baseline, remain stable or decline are useful for decision-making. There are many suitable rigorously validated PRO measures to consider if we are serious about charting the multiple, putative harms and benefits of novel drugs. Both the FDA and the EMA have recognized the need and published guidance on measures they would consider for label claims [9.US Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labelling ClaimsSilver Spring, MDUS Food and Drug Administration 2009; http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf (14 October 2018, date last accessed).Google Scholar, 10.European Medicines Agency, EMA. Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products 2005; http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC (14 October 2018, date last accessed).Google Scholar]. Trialists might also think about including the PROs version of the CTCAE (PRO-CTCAE) developed by the US National Cancer Institute (NCI) initiative to introduce patient-reported outcomes as a standard component of adverse event monitoring in NCI-sponsored trials [11.National Cancer Institute. Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™); https://healthcaredelivery.cancer.gov/pro-ctcae/ (14 October 2018, date last accessed).Google Scholar]. Any end point in a clinical trial requires thought, and it is important to challenge the cynical viewpoint still held by some that QoL end points are something that has to be included but is not really that pertinent for pharmacovigilance or decision-making. The unscientific approach of adding in any vaguely relevant measure to the trial protocol as an afterthought must end. Finally, if conducted well with employment of rigorous methodology, then proper respect should be given to the resultant patient-reported data that deserve to be published fully along with the main study results. None declared.