Assignment: meaningfulness of the endpoint to the clinician and to the patient

Assignment: meaningfulness of the endpoint to the clinician and to the patient ORDER NOW FOR CUSTOMIZED AND ORIGINAL ESSAY PAPERS ON Assignment: meaningfulness of the endpoint to the clinician and to the patient I’m trying to study for my Science course and I need some help to understand this question. Assignment: meaningfulness of the endpoint to the clinician and to the patient Please read the attached review (link below), and write a reflection on your own opinion as to the meaningfulness of event free survival to the cancer patient. Are there times where patients may feel this outcome is not connected to their illness or may not reflect their beliefs in what is important to them. EFS is a surrogate endpoint, and as such, would it meaningfully link to a physiological outcome of oncology treatment jamaoncology_raphael_2019_rv_190004.pdf Clinical Review & Education JAMA Oncology | Review The Value of Progression-Free Survival as a Treatment End Point Among Patients With Advanced Cancer A Systematic Review and Qualitative Assessment of the Literature Michael J. Raphael, MD, FRCPC; Andrew Robinson, MD, FRCPC; Christopher M. Booth, MD, FRCPC; Jennifer O’Donnell, BScH; Michael Palmer, MSc; Elizabeth Eisenhauer, MD, FRCPC; Michael Brundage, MD, FRCPC Supplemental content IMPORTANCE It is unclear whether patients with advanced cancer value surrogate end points, particularly progression-free survival (PFS). Despite this uncertainty, surrogate end points form the basis of regulatory approval for the majority of new cancer treatments. OBJECTIVE To summarize and qualitatively assess studies evaluating whether patients with advanced cancer understand and value PFS. EVIDENCE REVIEW MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature databases were searched from database inception to November 12, 2018. Articles eligible for inclusion investigated patient understanding, preference, or perceived value of disease progression or PFS in the setting of advanced cancer. Three authors independently reviewed and extracted data from all studies eligible for inclusion. FINDINGS In total, 17 studies representing 3646 patients were included. Of these studies, 15 specifically aimed to assess patients’ values toward, and their willingness to trade off toxic effects for gains or losses in the end point of PFS. All studies examined used widely disparate definitions when attempting to describe the meaning of PFS to patients. Ten studies specifically presented patients with the term progression-free survival as an attribute choice. In the words used to define the attribute of PFS, 6 studies used the term survival. Five studies clarified that PFS may not translate into better overall survival, and 5 studies explained that improvements in PFS may not reflect how well the patient may feel. No study clarified that a PFS event could represent either progression or death, and no study defined for the patient what constituted progression. The studies assessed herein underrepresented ethnic and racial minorities (mean percentage of white patients, 88%; range, 77%-96%). Values and preferences may vary across cultural backgrounds given that different relative preferences were assigned to cost and efficacy outcomes in North American vs Asian studies, although only a few studies were evaluated. CONCLUSIONS AND RELEVANCE The existing literature evaluating patients’ understanding, preferences, and values toward the end point of PFS was severely limited by the heterogeneity of methods, attribute selection, and descriptions used to define PFS to patients. High-quality studies are needed that clearly define PFS for patients and that systematically document their understanding of the term. Only then can it be assessed whether PFS is an end point of value to patients with advanced cancer. JAMA Oncol. 2019;5(12):1779-1789. doi:10.1001/jamaoncol.2019.3338 Published online September 26, 2019. Author Affiliations: Division of Cancer Care and Epidemiology, Queen’s Cancer Research Institute, Kingston, Ontario, Canada (Raphael, Robinson, Booth, O’Donnell, Palmer, Brundage); Assignment: meaningfulness of the endpoint to the clinician and to the patient Department of Oncology, Queen’s University, Kingston, Ontario, Canada (Raphael, Booth, Eisenhauer, Brundage); Department of Public Health Sciences, Queen’s University, Kingston, Ontario, Canada (Booth, Brundage). Corresponding Author: Michael Brundage, MD, Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, 10 Stuart St, Kingston, ON K7L 3N6, Canada (michael.brundage@ kingstonhsc.ca). (Reprinted) 1779 © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Columbia University Libraries User on 02/14/2020 Clinical Review & Education Review The Value of Progression-Free Survival as a Treatment End Point Among Patients With Advanced Cancer S ystemic cancer treatments should help patients live longer or better lives, and preferably, both. Therefore, overall survival and quality of life are clearly the 2 most meaningful patient-centered end points to establish the efficacy of new systemic cancer treatments. Because some researchers argue that it may be difficult and resource intensive to measure overall survival and quality of life, surrogate end points that can be measured more easily, with less cost, and less time are increasingly used.1,2 Putative surrogate end points, such as response rate and progression-free survival (PFS), are used based on the assumptions that shrinkage or delayed growth of cancer correlates with better overall survival or quality of life. Unfortunately, for most cancer types and treatments, these assumptions have not been proven.3-6 Despite this lack of evidence, surrogate end points form the basis of regulatory approval by the US Food and Drug Administration and by the European Medicines Agency for the majority of new cancer treatments.7-9 Whether regulatory approval and adoption of therapies should be based only on demonstrated meaningful improvements in overall survival or quality of life, or on established surrogates of these outcomes, is an important policy question. Although response rate and PFS may not be established surrogates for overall survival or quality of life for most cancer types, it does not automatically follow that these outcomes lack value to patients. Patients may choose to pursue treatments that shrink their cancer or delay its progression even if it comes at the expense of worsened quality of life and no overall survival benefit. Pursuing these gains may reflect the genuine values, preferences, and beliefs of patients regardless of the perceived rationality to physicians and policy makers.10 It is unclear whether patients with advanced cancer understand and value surrogate end points, particularly PFS. To evaluate the extent to which this important gap is addressed by the literature, we undertook a formal systematic review to summarize and to qualitatively assess studies evaluating the value of PFS among patients with advanced cancer. Methods Literature Search This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. 11 The present study relied exclusively on published literature; therefore, consistent with the guidelines of Queen’s University, Kingston, Ontario, Canada, the study was exempt from the need for formal review or ethics approval. A 3-step strategy was used to search the literature. In the first step, known items were analyzed for their subject headings and keywords. These terms were then used to perform a systematic search of the literature, which was conducted by a librarian. The search strategy was peer reviewed by a second librarian. MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature databases were searched (database inception to November 12, 2018). After selecting articles for inclusion, the reference lists were checked for any additional relevant studies. 1780 Key Points Question Assignment: meaningfulness of the endpoint to the clinician and to the patient Do patients with advanced cancer value progression-free survival as a cancer treatment end point? Findings This systematic review qualitatively assessed 17 articles representing 3646 patients with advanced cancer that evaluated their understanding, preferences, and values toward progression-free survival as a treatment end point. However, heterogeneity of methods, attribute selection, and definitions of progression-free survival given to patients across the studies limited the ability to interpret the results. Meaning High-quality studies are needed that clearly define progression-free survival for patients with advanced cancer and systematically document their understanding of the term to assess whether progression-free survival is of value to them. Inclusion and Exclusion Criteria Abstracts were reviewed by 2 investigators for inclusion (A.R. and J.O.). Articles were eligible for inclusion if they explored patients’ understanding, preference, or perceived value of disease progression or PFS in the setting of advanced cancer. Articles were excluded if they were review, opinion, or method articles, were published only as an abstract, evaluated nonsystemic interventions, were predominantly regarding patients in early curable disease, or described patterns of care. Data Abstraction This systematic review aggregated both quantitative and qualitative data. From each study, data were extracted independently into an electronic database in triplicate (M.J.R., J.O.D., and M.P.) and compared to ensure interinvestigator agreement. All disagreements were resolved by consensus. Variables to capture were decided a priori by the research team and iteratively adapted following pilot abstraction trials. Variables collected included cancer type, respondent information, funding, tradeoff method, pilot testing of attributes, definitions of PFS, relative or ranked attribute preferences, marginal rate of substitution calculations, and the benefits, risks, and costs explored. There is no uniformly accepted manner for how PFS should be described to patients. Based on a review of the literature and information from patient interviews from an ongoing pilot study by members of our group, we identified elements of the definition of PFS that we felt were important to ensure clarity and comprehension for patients. Extracting Ranked Attribute Preferences In studies using qualitative methods (eg, focus groups), the relative attribute ranking was determined by evaluating the percentage of patients who described each attribute as most important (highest rank) to least important (lowest rank). In discrete choice experiments (DCE) patients are presented with several choice sets in which the attribute levels are varied. For example, a patient may be presented with a choice between medication A, which results in a PFS of 10 months and carries a risk of grade 3 to 4 diarrhea of 10%, vs medication B, which results in a PFS of 8 months and carries a risk of grade 3 to 4 diarrhea of 2%. By systematically varying the attribute levels of PFS, diarrhea, and JAMA Oncology December 2019 Volume 5, Number 12 (Reprinted) © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Columbia University Libraries User on 02/14/2020 jamaoncology.com The Value of Progression-Free Survival as a Treatment End Point Among Patients With Advanced Cancer any other potential benefits and risks of the treatment, investigators can estimate the relative importance (“preference weight”) patients assign to each attribute or outcome using regression techniques.12,13 Marginal rate of substitution type calculations can then quantify the amount of value (eg, PFS time) Assignment: meaningfulness of the endpoint to the clinician and to the patient a patient is willing to forgo or “trade off” to reduce toxic effects (eg, diarrhea). In the studies using a DCE, if the authors did not state the ranked relative importance of each attribute, we evaluated the regression model coefficients for each level of the attribute, or measured the vertical distance between the preference weights in preference weight graphs, comparing the best and worst level of each attribute, to deduce this ranking. 12 Crossstudy comparison of relative attribute preferences for DCE is not valid because the preferences can only be meaningfully interpreted relative to the other attributes included in the statistical model. In addition, the elicited preferences are only applicable over the range of attribute levels used in the study.12 For those reasons, the study results were not quantitatively aggregated in the present study. Results Search Strategy The search strategy yielded 4881 publications of which 137 appeared to meet the inclusion criteria based on screening of the title (eFigure in the Supplement). Following detailed review of 137 abstracts, 22 articles were found to specifically assess patient understanding, preferences, or values regarding the end points of tumor progression or PFS and were thus potentially eligible for inclusion in the present study. After detailed review of these 22 full manuscripts, 5 studies were excluded because they presented only the physician perspective,14 data for adjuvant therapy,15,16 or no original information on PFS.17 Characteristics of Studies The characteristics of the 17 studies included in the final cohort are summarized in Table 1. Broadly, the studies used 3 methods to assess patient value of PFS. Two studies18,19 used informal, qualitative methods, including moderated focus groups and patient interviews, to explore which end points were meaningful to patients. Nine studies used formal tradeoff methods in which overall survival was not included as an anchoring attribute choice (ie, PFS was the only efficacy end point choice option).20-28 Six studies used formal tradeoff methods that did include overall survival as an anchoring attribute choice (ie, as a comparison or contrast to PFS29-31) or fixed the length of overall survival for a given PFS (ie, for a given level of PFS, patients were told that the overall survival was fixed at a specific number of months).32-34 All but 2 studies18,22 assessed patient values at a single time point. All but 3 studies18,19,22 used hypothetical choice sets in which the patients were asked to picture themselves in a situation in which they needed treatment and had to choose between 2 treatment options based on the risks and benefits presented. Patients were recruited from ambulatory clinics in 7 studies18,19,21-23,25,27 and online in 9 studies (via an external research agency20,29-31,34 or via emails from patient advocacy organizations24,28,32,33). The mechanism of recruitment was not stated in 1 study.26 jamaoncology.com Review Clinical Review & Education Characteristics of Patients The characteristics of the patient respondents are summarized in Table 1. The distribution of ethnicity/race was reported only in studies conducted in the United States;19,21,28,31-33 patients of ethnic/racial minority were significantly underrepresented (mean percentage white patients, 88%; range, 77%-96%). Among studies reporting the percentage of patients on active treatment at the time of value assessment, the range was from 12% 2 5 to 100%.18,19,22 Six studies23,26,27,29-31 did not report the percentage of patients on active treatment. Definitions of PFS Used When Assessing Patients’ Preferences Fifteen of the 17 studies specifically aimed to assess the value patients placed on PFS and their willingness to trade off toxic effects of treatment for gains or losses in PFS. The studies examined used widely disparate definitions when attempting to describe the meaning of PFS to patients (eTable in the Supplement). All but 2 studies22,32 described performing a pretest to assess the clarity of the presented attributes. It was apparent from the results of these pretests that patients had difficulty fully understanding the concept of PFS and how it differed from time to tumor progression and overall survival. Only the study by Bridges et al29(p226) specifically commented on patient understanding of the term PFS: “Patients indicated in pretest interviews that they best understood the meaning of PFS as time to disease progression. Patients were unaware of the statistical difference between these 2 clinical measures.”Assignment: meaningfulness of the endpoint to the clinician and to the patient The elements used for the clarification and specification of the term PFS are detailed in Table 2. Of the 15 studies, 10 specifically presented patients with the term progression-free survival as an attribute in their choice set scenarios; in the definition, the term survival was used in 6 studies. No study clarified that a PFS event could represent either progression or death, and no study defined what constituted progression (eg, radiologic-based or other criteria). Five studies clarified that PFS may not translate into better overall survival. Five studies clarified that improvements in PFS may not reflect how well a patient may feel. Six studies provided a clearly separate overall survival attribute for comparison with varying levels of PFS. Ranked Importance of Presented Attributes The attributes evaluated and their relative importance are presented in Table 3. Six studies20,21,23,25,26,28 in which overall survival was not fixed or not provided as an anchoring comparison attribute presented information that enabled ranking of the relative importance of attributes, which included PFS. Progression-free survival was ranked as the most important attribute in 2 of these studies.21,28 In the study by González et al,20 when the risk of adverse events was presented at high levels (eg, risk of cardiopulmonary arrest, 20%; risk of serious hemorrhage, 30%), these adverse events were ranked as most important. When those risks were limited to the clinically relevant range (risk of 2% each), PFS was ranked as most important. In the remaining 3 studies,23,25,26 which all took place in Asia, PFS was never ranked as most important. Six studies with overall survival provided as an anchoring comparison attribute30-32 or fixed for a given duration of PFS29,33,34 presented information that enabled ranking of the relative importance of PFS. In studies in which the patient could select overall survival as an attribute to rank,30-32 it was always selected as the most (Reprinted) JAMA Oncology December 2019 Volume 5, Number 12 © 2019 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Columbia University Libraries User on 02/14/2020 1781 Clinical Review & Education Review The Value of Progression-Free Survival as a Treatment End Point Among Patients With Advanced Cancer Table 1. Summary of Studies Evaluating the Value of Progression-Free Survival Among Patients With Advanced Cancer Source Location Sponsor/ Funding Cancer Site and Patient Characteristics Recruitment and Main Methods Treatment to Tradeoff Benefits/Risks to Tradeoff Cohort 1: Studies With Informal Tradeoff Methods Beesley et al, 201018 Australia Academic Ovarian cancer New diagnosis or relapse n = 122 Median age, 61 y Active treatment, all Recruited in ambulatory clinic Baseline interview Follow-up surveys with each cycle, up to 2 y Chemotherapy Tumor shrinkage Delay in progression Symptom improvement Treatment toxic effects Beliefs about cure Gerber et al, 201219 United States Academic Lung cancer Stage IV n = 13 Mean age, 60 y Active treatment, all White, 77% Recruited in ambulatory clinic Moderated focus groups with thematic content analysis Single evaluation Maintenance chemotherapy Survival benefits Disease control “Buying time” “Doing something” QOL Cohort 2: Studies With Formal Tradeoff Methods, Not Anchored by Overall Survival González et al, 201720 United States Pharma Colon cancer (self-report) Metastatic n = 127 Mean age, 46 y Active treatment, 65% Recruited online by research company DCE with 9 choice sets Single evaluation Anti-VEGF and anti-EGFR antibodies PFS (6, 8, 12 mo) Skin rash Bleeding Gastrointestinal perforation Heart attack Havrilesky et al, 201421 United States Academic Ovarian cancer Stage III/IV n = 95 Mean age, 60 y Active treatment, 52% White, 85% Recruited in ambulatory clinic Likert scale rankings of benefits/risks importance DCE with 12 choice sets Single evaluation Chemotherapy PFS (15, 18, 21, 24 mo) Abdominal symptoms Nausea/vomiting Neuropathy Fatigue Route of administration Visit frequency Jenkins et al, 201822 United Kingdom Pharma Multiple cancer sites Metastatic disease n = 90 Mean age, 65 y Active tre … Assignment: meaningfulness of the endpoint to the clinician and to the patient Get a 10 % discount on an order above $ 100 Use the following coupon code : NURSING10