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Correspondence: Fabio Efficace, PhD, Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), GIMEMA Data Center, Via Benevento, 6, 00161 - Rome, Italy.
French National Platform Quality of Life and Cancer, Besançon, FranceMethodology and Quality of Life in Oncology Unit (INSERM UMR 1098), University Hospital of Besançon, Besançon, France
Do patient-reported outcomes (PROs) provide independent prognostic information for overall survival beyond clinical and laboratory factors typically used when making prognosis in oncology?
•
Overall, 138 studies including 158 127 patients were found. Of these, 120 (87%) studies reported at least one PRO to be statistically significantly prognostic for overall survival. Lung (n = 41, 29.7%) and genitourinary (n = 27, 19.6%) cancers were most commonly investigated.
•
There is convincing evidence that PROs provide independent prognostic information for overall survival across cancer populations and disease stages. However, further research is needed to translate current evidence-based data into prognostic tools to aid in clinical decision making.
Abstract
Objectives
Assessment of patient-reported outcomes (PROs) in oncology is of critical importance because it provides unique information that may also predict clinical outcomes.
Methods
We conducted a systematic review of prognostic factor studies to examine the prognostic value of PROs for survival in cancer. A systematic literature search was performed in PubMed for studies published between 2013 and 2018. We considered any study, regardless of the research design, that included at least 1 PRO domain in the final multivariable prognostic model. The protocol (EPIPHANY) was published and registered in the International Prospective Register of Systematic Reviews (CRD42018099160).
Results
Eligibility criteria selected 138 studies including 158 127 patients, of which 43 studies were randomized, controlled trials. Overall, 120 (87%) studies reported at least 1 PRO to be statistically significantly prognostic for overall survival. Lung (n = 41, 29.7%) and genitourinary (n = 27, 19.6%) cancers were most commonly investigated. The prognostic value of PROs was investigated in secondary data analyses in 101 (73.2%) studies. The EORTC QLQ-C30 questionnaire was the most frequently used measure, and its physical functioning scale (range 0-100) the most frequent independent prognostic PRO, with a pooled hazard ratio estimate of 0.88 per 10-point increase (95% CI 0.84-0.92).
Conclusions
There is convincing evidence that PROs provide independent prognostic information for overall survival across cancer populations and disease stages. Further research is needed to translate current evidence-based data into prognostic tools to aid in clinical decision making.
Patient-reported outcome (PRO) measures have historically been included in cancer clinical trials as treatment outcomes to complement information obtained via more traditional clinical and survival indicators.
Quality of patient-reported outcome reporting across cancer randomized controlled trials according to the CONSORT patient-reported outcome extension: a pooled analysis of 557 trials.
PROs also have an established application in daily routine oncology practice. There is now convincing evidence that the systematic integration of PRO assessment in the oncology clinic is associated with patient benefits such as improved symptom control, patient–physician communication, satisfaction with care, and survival outcomes.
Identification and interpretation of clinical and quality of life prognostic factors for survival and response to treatment in first-line chemotherapy in advanced breast cancer.
has shown that health status information gathered through validated PRO measures provides prognostic information beyond the traditional indicators typically used in oncology, such as performance status. Three systematic reviews focused mainly on randomized, controlled trials (RCTs) have documented the independent prognostic value of PRO domains such as symptoms, global health status, and functional limitations for overall survival.
The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
was the most frequently used questionnaire in this area. However, none of the studies identified a clear set of PRO domains that frequently emerge to predict survival in a given cancer population. Critical appraisal of how such evidence can be implemented in real-world practice has thus been limited.
To the best of our knowledge, no state-of-the-art information is available on the amount and quality of research on the prognostic value of PROs for overall survival across all possible research designs (eg, observational studies). Such information is critical to better understand how this wealth of evidence could impact real-life practice and more accurately inform prognosis in routine cancer care.
We performed a systematic review of recently conducted studies, regardless of the research design, to investigate the value of PROs in prognostic models predicting overall survival in cancer. We also hypothesized that the EORTC QLQ-C30 was still the most frequently used PRO measure in this area. We therefore examined which PRO domains from the EORTC QLQ-C30 were most frequently included in prognostic models for overall survival.
Materials and Methods
Search Strategy and Selection Criteria
The protocol for this project (EPIPHANY) was published
Evaluating methodological quality of prognostic models including patient-reported health outcomes in oncology (EPIPHANY): a systematic review protocol.
and registered in the International Prospective Register of Systematic Reviews (CRD42018099160). A systematic literature search was performed in PubMed for studies published between January 2013 and February 2018. The keywords used for the PubMed search strategy can be found in Appendix 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2020.10.017.
In accordance with the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS),
we included prognostic model development studies with and without external data validation and studies focused solely on model validation. We included studies on adult patients with cancer (≥18 years) that predicted overall survival and included at least 1 baseline PRO as a predictor in the final multivariable prognostic model. We considered any type of study regardless of research design, including both observational studies and clinical trials (including RCTs).
Studies were excluded when the association between baseline PROs and overall survival was examined in a univariate or unadjusted analysis only. Studies were excluded if they only considered PRO change scores over time as potential prognostic variables during model development. We only considered articles published in English and omitted literature such as reviews, commentaries, and working papers.
Data Collection
The data were collected electronically through the Research Electronic Data Capture platform (REDCap, Vanderbilt University; https://www.project-redcap.org/).
Research electronic data capture (REDCap): a metadata-driven methodology and workflow process for providing translational research informatics support.
For each study meeting the inclusion criteria, 2 of the 6 reviewers independently extracted the information from each article. In case of discrepancies, the reviewers discussed the article to reconcile any differences until consensus was achieved. If necessary, a third senior reviewer was consulted to facilitate the reconciliation process. Each reviewer was issued a personal password to access the web database, where they completed electronic data extraction form for each article. This form collected information on study characteristics, PROs, and multivariable model development.
Data Analysis
Several types of information were analyzed: characteristics of the study design, cancer population, statistical methodology, number of covariates used in the prognostic model, PRO measures, and prognostic findings. For descriptive purposes, we summarized the characteristics and prognostic findings for the PROs of each eligible study separately per cancer stage. We categorized study populations as metastatic/advanced or nonmetastatic/loco-regional if at least 80% of the patients were reported as belonging to 1 of these 2 categories. If less than 80% belonged to either group or if cancer stage was not defined, we classified the study population as mixed or unclear.
If more than one prognostic model with PROs was developed in the same study, we assessed the model with the most predictors. We classified the prognostic PRO data analysis as primary when it was reported as the original study’s primary or secondary objective. Otherwise, we classified the PRO data analysis as secondary—for example, if it involved secondary data analyses of previously conducted RCTs.
We summarized the overall prevalence of the PRO measures used by frequencies and proportions. Based on the results, we also assessed the overall prevalence of each EORTC QLQ-C30 questionnaire scale to identify which were more frequently investigated as prognostic factors for overall survival. The QLQ-C30 physical functioning scale, which was most frequently associated with overall survival, was included in a meta-analysis to assess its prognostic influence on overall survival, including only those studies reporting continuous PRO predictors. For each study included in the meta-analysis, we reported the corresponding PRO’s hazard ratio and 95% confidence interval as per 1-point increase in the score of the scale (overall range 0-100). All hazard ratios were weighted and pooled using a random-effects model to account for the heterogeneity in the patient populations. All analyses were performed using SAS software version 9.4 (SAS Institute Inc, Cary, NC) or R software version 3.5.2.
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement when reporting our study.
Net clinical benefit analysis of radiation therapy oncology group 0525: a phase III trial comparing conventional adjuvant temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma.
Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial.
Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer.
The association between health-related quality-of-life scores and clinical outcomes in metastatic castration-resistant prostate cancer patients: exploratory analyses of AFFIRM and PREVAIL studies.
Role functioning before start of adjuvant treatment was an independent prognostic factor for survival and time to failure: a report from the Nordic adjuvant interferon trial for patients with high-risk melanoma.
Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302.
Prediction of quality of life and survival after surgery for symptomatic spinal metastases: a multicenter cohort study to determine suitability for surgical treatment.
Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome.
Could baseline health-related quality of life (QoL) predict overall survival in metastatic colorectal cancer? The results of the GERCOR OPTIMOX 1 study.
Prognostic value of self-reported fatigue on overall survival in patients with myelodysplastic syndromes: a multicentre, prospective, observational, cohort study.
Development of a geriatric vulnerability score in elderly patients with advanced ovarian cancer treated with first-line carboplatin: a GINECO prospective trial.
Prognostic factor analysis of overall survival in gastric cancer from two phase III studies of second-line ramucirumab (REGARD and RAINBOW) using pooled patient data.
Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer.
Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial.
Prognostic factors for survival in noncastrate metastatic prostate cancer: validation of the glass model and development of a novel simplified prognostic model.
Patients with oesophageal cancer report elevated distress and problems yet do not have an explicit wish for referral prior to receiving their medical treatment plan.
Baseline measure of health-related quality of life (functional assessment of cancer therapy-esophagus) is associated with overall survival in patients with esophageal cancer.
Social networks, social support, and burden in relationships, and mortality after breast cancer diagnosis in the Life After Breast Cancer Epidemiology (LACE) study.
Prognostic factors in patients with advanced cancer: a comparison of clinicopathological factors and the development of an inflammation-based prognostic system.
Prognostic values of EORTC QLQ-C30 and QLQ-HCC18 index-scores in patients with hepatocellular carcinoma: clinical application of health-related quality-of-life data.
The relationship between patient satisfaction with service quality and survival in non-small-cell lung cancer: is self-rated health a potential confounder?.
The Phase 3 COU-AA-302 study of abiraterone acetate plus prednisone in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: stratified analysis based on pain, prostate-specific antigen, and Gleason score.
Depressive symptoms are a risk factor for all-cause mortality: results from a prospective population-based study among 3,080 cancer survivors from the PROFILES registry.
Quality of life analysis of a radiation dose-escalation study of patients with non-small-cell lung cancer: a secondary analysis of the Radiation Therapy Oncology Group 0617 randomized clinical trial.
Prediction of survival by pretreatment health-related quality-of-life scores in a prospective cohort of patients with head and neck squamous cell carcinoma.
The association of financial difficulties with clinical outcomes in cancer patients: secondary analysis of 16 academic prospective clinical trials conducted in Italy.
Quality of life is significantly associated with survival in women with advanced epithelial ovarian cancer: an ancillary data analysis of the NRG Oncology/Gynecologic Oncology Group (GOG-0218) study.
Helplessness/hopelessness, minimization and optimism predict survival in women with invasive ovarian cancer: a role for targeted support during initial treatment decision-making?.
Effect of p16 status on the quality-of-life experience during chemoradiation for locally advanced oropharyngeal cancer: a substudy of randomized trial Trans-Tasman Radiation Oncology Group (TROG) 02.02 (HeadSTART).
Reducing uncertainty: predictors of stopping chemotherapy early and shortened survival time in platinum resistant/refractory ovarian cancer—the GCIG Symptom Benefit Study.
Longitudinal alterations in health-related quality of life and its impact on the clinical course of patients with advanced hepatocellular carcinoma receiving sorafenib treatment.
Simplified graded baseline symptom assessment in patients with lung cancer undergoing first-line chemotherapy: correlations and prognostic role in a resource-constrained setting.
Patient-reported pain and other quality of life domains as prognostic factors for survival in a phase III clinical trial of patients with advanced breast cancer.
Quality of life analyses from the randomized, open-label, phase III PointBreak study of pemetrexed-carboplatin-bevacizumab followed by maintenance pemetrexed-bevacizumab versus paclitaxel-carboplatin-bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer.
Creation of a prognostic index for spine metastasis to stratify survival in patients treated with spinal stereotactic radiosurgery: secondary analysis of mature prospective trials.
Quality of life and performance status from a substudy conducted within a prospective phase 3 randomized trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for locally advanced head and neck carcinoma: NRG Oncology Radiation Therapy Oncology Group 0522.
Significance of baseline and change in quality of life scores in predicting clinical outcomes in an international phase III trial of advanced pancreatic cancer: NCIC CTG PA.3.
Anxiety after diagnosis predicts lung cancer-specific and overall survival in patients with stage III non-small cell lung cancer: a population-based cohort study.
Physical function and quality of life in frail and/or elderly patients with metastatic colorectal cancer treated with capecitabine and bevacizumab: an exploratory analysis.
Health-related quality of life and risk of colorectal cancer recurrence and all-cause death among advanced stages of colorectal cancer 1-year after diagnosis.
Quality of life and performance status from a substudy conducted within a prospective phase 3 randomized trial of concurrent standard radiation versus accelerated radiation plus cisplatin for locally advanced head and neck carcinoma: NRG Oncology RTOG 0129.
Prospective longitudinal quality of life and survival outcomes in patients with advanced infiltrative hepatocellular carcinoma and portal vein thrombosis treated with Yttrium-90 radioembolization.
The identification and selection of the studies included in this review is reported in a Preferred Reporting Items for Systematic Reviews and Meta-Analysis flowchart (see Appendix 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2020.10.017). One hundred and twenty (87.0%) studies reported at least 1 PRO to be statistically significantly prognostic for overall survival in the final multivariable prognostic model.
Overview of Study Characteristics
Sixty-four (46.4%) studies included patients with primarily metastatic/advanced cancer, 32 (23.2%) included patients with primarily nonmetastatic/loco-regional cancer, and the remaining 42 (30.4%) included a population with mixed or unclear disease stages. Of these, 57 of 64 (89.1%) of metastatic/advanced studies, 28 of 32 (87.5%) of loco-regional/nonmetastatic studies, and 35 of 42 (83.3%) of mixed cancer population studies reported at least 1 PRO that could independently predict survival.
Most studies (n = 94, 68.1%) had a follow-up time of more than 24 months, with a 54 % average event rate computed from 91 studies that reported this information. The prognostic value of PROs was investigated in secondary data analyses in 101 (73.2%) studies, of which 43 were retrospective analyses of RCTs. Almost all studies (n = 136, 98.6%) used the Cox proportional hazards model. Only 26 (21.7%) studies validated the final multivariable model in separate datasets or with internal validation techniques. Further details are reported in Table 1.
Table 1Characteristics of prognostic factor studies including PROs (N = 138).
When studies included metastatic and nonmetastatic patients, the study was classified as metastatic or nonmetastatic when at least 80% of the patients fell into that category.
Primarily metastatic/advanced cancer
64 (46.4)
Primarily nonmetastatic/loco-regional cancer
32 (23.2)
Mixed/unclear cancer stage
42 (30.4)
Number of covariates considered before model building, in addition to PROs
PRO data analysis was classified as primary when it was planned as the primary or secondary objective of the study. All other PRO data analyses were classified as secondary. For example, secondary data analyses of previously conducted randomized, controlled trials were considered secondary.
Frequencies are based on studies reporting an independent prognostic value of PROs for overall survival. Validation denotes the use of internal (eg, resampling techniques, bootstrap) or external (eg, new population setting) validation.
Yes
26 (21.7)
No
94 (78.3)
∗ When studies included metastatic and nonmetastatic patients, the study was classified as metastatic or nonmetastatic when at least 80% of the patients fell into that category.
† Number of patients refers to those included in prognostic model development.
‡ PRO data analysis was classified as primary when it was planned as the primary or secondary objective of the study. All other PRO data analyses were classified as secondary. For example, secondary data analyses of previously conducted randomized, controlled trials were considered secondary.
§ Frequencies are based on studies reporting an independent prognostic value of PROs for overall survival. Validation denotes the use of internal (eg, resampling techniques, bootstrap) or external (eg, new population setting) validation.
Cancer Populations and Patterns of Prognostic PRO Domains
Each of the 138 selected studies could be based on 1 or more cancer populations, assessing PROs by a single measure or by multiple measures. The most commonly investigated cancers were lung (n = 41, 29.7%), genitourinary (n = 27, 19.6%), esophagogastric (n = 25, 18.1%), and breast (n = 24, 17.4%) cancer. Figure 1 shows the 10 most frequently investigated cancers.
Figure 1Top 10 cancer types investigated in multivariable prognostic models with patient-reported outcomes. More than one cancer type can be present in 1 study.
Several types of PRO domains were found to be prognostic within each cancer group. For example, more than 20 PROs were found to be independent predictors of overall survival in patients diagnosed with lung cancer.
Performance status was found to be statistically significant in final multivariable models in 34 studies (24.6%). PROs were also statistically significant in the models of 32 (94%) of these studies.
The full list of studies by cancer diagnosis is provided in Table 2.
Table 2Study characteristics, measures, and results.
Net clinical benefit analysis of radiation therapy oncology group 0525: a phase III trial comparing conventional adjuvant temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma.
Social networks, social support, and burden in relationships, and mortality after breast cancer diagnosis in the Life After Breast Cancer Epidemiology (LACE) study.
Patient-reported pain and other quality of life domains as prognostic factors for survival in a phase III clinical trial of patients with advanced breast cancer.
Could baseline health-related quality of life (QoL) predict overall survival in metastatic colorectal cancer? The results of the GERCOR OPTIMOX 1 study.
Physical function and quality of life in frail and/or elderly patients with metastatic colorectal cancer treated with capecitabine and bevacizumab: an exploratory analysis.
Health-related quality of life and risk of colorectal cancer recurrence and all-cause death among advanced stages of colorectal cancer 1-year after diagnosis.
Baseline measure of health-related quality of life (functional assessment of cancer therapy-esophagus) is associated with overall survival in patients with esophageal cancer.
Health-related quality of life results from the PRODIGE 5/ACCORD 17 randomised trial of FOLFOX versus fluorouracil-cisplatin regimen in oesophageal cancer.
Prognostic factor analysis of overall survival in gastric cancer from two phase III studies of second-line ramucirumab (REGARD and RAINBOW) using pooled patient data.
Patients with oesophageal cancer report elevated distress and problems yet do not have an explicit wish for referral prior to receiving their medical treatment plan.
Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial.
Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer.
Prognostic factors for survival in noncastrate metastatic prostate cancer: validation of the glass model and development of a novel simplified prognostic model.
The association between health-related quality-of-life scores and clinical outcomes in metastatic castration-resistant prostate cancer patients: exploratory analyses of AFFIRM and PREVAIL studies.
The association between health-related quality-of-life scores and clinical outcomes in metastatic castration-resistant prostate cancer patients: exploratory analyses of AFFIRM and PREVAIL studies.
Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302.
Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302.
The Phase 3 COU-AA-302 study of abiraterone acetate plus prednisone in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: stratified analysis based on pain, prostate-specific antigen, and Gleason score.
Development of a geriatric vulnerability score in elderly patients with advanced ovarian cancer treated with first-line carboplatin: a GINECO prospective trial.
Helplessness/hopelessness, minimization and optimism predict survival in women with invasive ovarian cancer: a role for targeted support during initial treatment decision-making?.
Quality of life is significantly associated with survival in women with advanced epithelial ovarian cancer: an ancillary data analysis of the NRG Oncology/Gynecologic Oncology Group (GOG-0218) study.
Reducing uncertainty: predictors of stopping chemotherapy early and shortened survival time in platinum resistant/refractory ovarian cancer—the GCIG Symptom Benefit Study.
Prediction of survival by pretreatment health-related quality-of-life scores in a prospective cohort of patients with head and neck squamous cell carcinoma.
Effect of p16 status on the quality-of-life experience during chemoradiation for locally advanced oropharyngeal cancer: a substudy of randomized trial Trans-Tasman Radiation Oncology Group (TROG) 02.02 (HeadSTART).
Quality of life and performance status from a substudy conducted within a prospective phase 3 randomized trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for locally advanced head and neck carcinoma: NRG Oncology Radiation Therapy Oncology Group 0522.
Quality of life and performance status from a substudy conducted within a prospective phase 3 randomized trial of concurrent standard radiation versus accelerated radiation plus cisplatin for locally advanced head and neck carcinoma: NRG Oncology RTOG 0129.
Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome.
Prognostic value of self-reported fatigue on overall survival in patients with myelodysplastic syndromes: a multicentre, prospective, observational, cohort study.
Longitudinal alterations in health-related quality of life and its impact on the clinical course of patients with advanced hepatocellular carcinoma receiving sorafenib treatment.
Prognostic values of EORTC QLQ-C30 and QLQ-HCC18 index-scores in patients with hepatocellular carcinoma: clinical application of health-related quality-of-life data.
Prospective longitudinal quality of life and survival outcomes in patients with advanced infiltrative hepatocellular carcinoma and portal vein thrombosis treated with Yttrium-90 radioembolization.
The relationship between patient satisfaction with service quality and survival in non-small-cell lung cancer: is self-rated health a potential confounder?.
Quality of life analyses from the randomized, open-label, phase III PointBreak study of pemetrexed-carboplatin-bevacizumab followed by maintenance pemetrexed-bevacizumab versus paclitaxel-carboplatin-bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer.
Quality of life analysis of a radiation dose-escalation study of patients with non-small-cell lung cancer: a secondary analysis of the Radiation Therapy Oncology Group 0617 randomized clinical trial.
Simplified graded baseline symptom assessment in patients with lung cancer undergoing first-line chemotherapy: correlations and prognostic role in a resource-constrained setting.
A separate multivariable model was developed for each PRO scale.
small-cell lung cancer, non-small-cell lung cancer
6290
Unclear/Not included
SF-36, Ad hoc PRO items measuring global HRQoL
Physical function, Role physical, Bodily pain, General health, Vitality, Social function, Role emotional, Mental health, Physical composite score, Mental composite score, Global HRQoL
Anxiety after diagnosis predicts lung cancer-specific and overall survival in patients with stage III non-small cell lung cancer: a population-based cohort study.
Role functioning before start of adjuvant treatment was an independent prognostic factor for survival and time to failure: a report from the Nordic adjuvant interferon trial for patients with high-risk melanoma.
Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial.
Significance of baseline and change in quality of life scores in predicting clinical outcomes in an international phase III trial of advanced pancreatic cancer: NCIC CTG PA.3.
Prognostic factors in patients with advanced cancer: a comparison of clinicopathological factors and the development of an inflammation-based prognostic system.
Depressive symptoms are a risk factor for all-cause mortality: results from a prospective population-based study among 3,080 cancer survivors from the PROFILES registry.
Prediction of quality of life and survival after surgery for symptomatic spinal metastases: a multicenter cohort study to determine suitability for surgical treatment.
Creation of a prognostic index for spine metastasis to stratify survival in patients treated with spinal stereotactic radiosurgery: secondary analysis of mature prospective trials.
including: genitourinary, breast, gynecological, gastrointestinal, liver, lung, pancreas and bile duct, head and neck, skin, sarcoma, central nervous system
The association of financial difficulties with clinical outcomes in cancer patients: secondary analysis of 16 academic prospective clinical trials conducted in Italy.
including: genitourinary, brain, central nervous system, breast, gynecological, gastrointestinal, head and neck, lung, soft tissue or bone, skin, lymph node
BFI indicates Brief Fatigue Inventory; BPI, Brief Pain Inventory; BPI-SF, Brief Pain Inventory–Short Form; BSI-18, Brief Symptom Inventory-18; CES-D, 60-point Center for Epidemiologic Studies Depression Scale: DT/PL, Distress Thermometer and Problem List; EORTC QLQ- BN20, EORTC Quality of Life Questionnaire – Brain Tumor Module; EORTC QLQ-BR23, EORTC Quality of Life Questionnaire – Breast Cancer Module; EORTC QLQ-C30, The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30; EORTC QLQ-C15-PAL, EORTC Quality of Life Questionnaire – Palliative Care Module; EORTC QLQ-HCC18, Hepatocellular Carcinoma/Primary Liver Cancer Module; EORTC QLQ-H&N35, EORTC Quality of Life Questionnaire – Head and Neck Cancer Module; EORTC QLQ-LC13, EORTC Quality of Life Questionnaire – Lung Cancer Module; EORTC QLQ-LMC21, EORTC Quality of Life Questionnaire – Liver Metastases Colorectal Module; EORTC QLQ-OES18, EORTC Quality of Life Questionnaire – Esophageal Cancer Module; EORTC QLQ-OV28, Ovarian Cancer Module; EORTC QLQ-STO22, EORTC Quality of Life Questionnaire – Gastric Cancer Module; EPQ, Eysenck Personality Questionnaire; EQ-5D, EuroQol-5D; EQ-5D-3L, EuroQol-5D-3L; ESAS, Edmonton Symptom Assessment Scale; FACT-BMT, Functional Assessment of Cancer Therapy – Bone Marrow Transplant; FACT-BR, Functional Assessment of Cancer Therapy – Brain; FACT-C, Functional Assessment of Cancer Therapy – Colorectal; FACT-E, Functional Assessment of Cancer Therapy – Esophageal; FACIT-F, Functional Assessment of Chronic Illness Therapy – Fatigue; FACT-F, Functional Assessment of Cancer Therapy – Fatigue; FACT-G, Functional Assessment of Cancer Therapy – General; FACT/GOG-Ntx, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity Questionnaire; FACT-Hep, Functional Assessment of Cancer Therapy – Hepatobiliary; FACT-H&N, Functional Assessment of Cancer Therapy – Head and Neck Cancer; FACT-L, Functional Assessment of Cancer Therapy – Lung; FACT-P, Functional Assessment of Cancer Therapy – Prostate; FACT-O, Functional Assessment of Cancer Therapy – Ovarian Cancer; GHQ-30, General Health Questionnaire-30; HADS, Hospital Anxiety and Depression Scale; HNRQ, Head and Neck Radiotherapy Questionnaire; LASA, Linear Analog Self-Assessment; LCSS, Lung Cancer Symptom Scale; MAC, Mental Adjustment to Cancer; MDADI, MD Anderson Dysphagia Inventory; MDASI, MD Anderson Symptom Inventory; MPQ, McGill Pain Questionnaire; MRS, Mood Rating Scale; PAT-D, Pepper Assessment Tool for Disability; PRD, Patient-Reported Distress Questionnaire; PRO-CCI, Patient-Reported Carlson Comorbidity Index; PSSCAN, Psychosocial Screen for Cancer; RSCL, Rotterdam Symptom Checklist; SF-12, Short Form-12; SF-36, Short Form-36; SQLI, Spitzer Quality of Life Index; VAS, Visual Analogue Scale.
∗ N refers to the number of patients included in the prognostic model development.
† No indicates not statistically significant in the final multivariable model for survival.
‡ A separate multivariable model was developed for each PRO scale.
§ Several models were developed, with varying numbers of covariates. We considered the model with the largest number of predictors.
A wide range of PRO measures were used across in the reviewed studies. The EORTC questionnaires were the most frequently used PRO measures (n = 56, 40.6%), followed by the FACT (n = 26, 18.8%) and SF-12/36 (n = 14, 10.1%) questionnaires. Figure 2 shows the 10 most frequently used measures.
Figure 2Top 10 patient-reported outcome measures used in multivariable prognostic models. More than one patient-reported outcome (PRO) measure could be used in 1 study. ∗The EORTC and FACT include core and disease-specific QLQ. The SF-36 category also includes studies that used the SF-12 in the prognostic model development.
BPI indicates Brief Pain Inventory; EORTC, European Organization for Research and Treatment of Cancer; EQ-5D, EuroQol-5D; ESAS, Edmonton Symptom Assessment System; FACT, Functional Assessment of Cancer Therapy; SF-36, Short Form Health Survey; HADS, Hospital Anxiety and Depression Scale; LCSS, Lung Cancer Symptom Scale; MDASI, MD Anderson Symptom Inventory; VAS, Visual Analogue Scale.
Most Frequent PRO Prognostic Scales of the EORTC QLQ-C30 Questionnaire
Of the 55 studies using the EORTC QLQ-C30 questionnaire, 41 (74.6%) reported at least 1 prognostic EORTC QLQ-C30 scale. Of these, the most frequently reported scales were physical functioning (n = 16, 39.0%), appetite loss and fatigue (each n = 7, 17.1%), and pain, dyspnea, and global quality of life/health status (each n = 6, 14.6%).
Sixteen studies reported continuous hazard ratios for the physical functioning scale. The scale was statistically significant in 11 of these multivariable models, and the pooled hazard ratio estimate of its prognostic value was 0.88 per 10-point increase (95% confidence interval, 0.84-0.92) (Fig. 3).
Figure 3Association between EORTC QLQ-C30 physical functioning scale and overall survival. The forest plots represent only those 16 studies that included the physical functioning scale in the final multivariable model as a continuous variable, regardless of its statistical significance. All hazard ratios are reported as per 1-point increase in the score of the scale. ∗Statistically significant according to the p value reported by the authors in the original article.
In studies with primarily metastatic/advanced cancer, there were 75% (6 out of 8) of multivariable models where physical functioning was statistically significant prognostic for overall survival. This proportion was also 75% (3 out of 4) in studies with primarily nonmetastatic/loco-regional cancer (details are reported in Appendix 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2020.10.017).
Discussion
We identified a remarkable number (N = 138) of prognostic oncology studies with PROs published in just 5 years. Around 90% of these studies found at least 1 PRO domain that predicted overall survival while controlling for key clinical and laboratory data.
This independent association between PRO and survival was demonstrated across many cancer populations, ranging from the most common solid malignancies to rare hematologic conditions such as myelodysplastic syndromes.
Prognostic value of self-reported fatigue on overall survival in patients with myelodysplastic syndromes: a multicentre, prospective, observational, cohort study.
It was also consistent across different types of research, including secondary analyses of RCTs and hypothesis-driven prospective observational studies, and a wide range of PRO measures, supporting the robustness of the association. We found that PROs provided independent prognostic information for patients both with advanced/metastatic and earlier stage diseases. These findings extend previous work, which documented the independent association between PROs and survival in selected patients enrolled in clinical trials and mainly with advanced/metastatic disease.
conducted a population-based study on 500 000 individuals to investigate 5-year predictors of mortality. Despite the sizable amount of clinical and laboratory data considered in their analysis, which used the large UK Biobank dataset, they concluded that self-reported health was the strongest predictor of all-cause mortality in men.
Although the mechanisms underlying the association between PROs and survival remains to be elucidated, our results provide convincing evidence that, at the very least, self-reported health status data provide unique prognostic information that is not captured with traditional clinical exams. Our findings strongly support the systematic integration of PRO data into routine practice, because PROs capture highly clinically relevant information.
We found that the EORTC QLQ-C30 was the most frequently used PRO measure and that its physical functioning scale emerged most often as an independent prognostic factor in multivariable analyses across various cancer populations, research designs, and treatment scenarios. A recent review also reported that this scale was the most frequent prognostic PRO domain in 44 cancer RCTs published between 2006 and 2018.
in newly diagnosed patients with multiple myeloma. They used a prognostic factor analysis that thoroughly considered several key disease-specific variables, such as β-2 microglobulin and extent of skeletal disease.
Our meta-analysis estimated the magnitude of the association between patient-reported physical functioning and overall survival and found a 12% increase in the risk of death for every 10-point decrease on this scale (range 0-100). This scale is thus highly sensitive for capturing key prognostic information and can inform the design of future studies investigating the prognostic value of PROs in oncology. Physical functioning could also be considered a stratification factor in future RCTs to enhance outcome interpretation. Although performance status has traditionally been used as a key stratification variable in cancer trials,
Patient characteristics and stratification in medical treatment studies for metastatic colorectal cancer: a proposal for standardization of patient characteristic reporting and stratification.
we found that physical functioning often superseded physician-reported performance status in multivariable analyses. Although both parameters are meant to indicate physical performance, the patient’s perspective is a more sensitive parameter.
Further work is required to establish clinically relevant thresholds to effectively stratify patients in future trials.
Our findings also emphasize the urgent need of a more rigorous and standardized approach, as well as thoughtful selection of sensitive PRO measures, to translate current evidence-based data into prognostic tools to aid in clinical decision making.
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