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Patient-Reported Symptoms for Esophageal Cancer Patients Undergoing Curative Intent Treatment
Journal Pre-proof Patient-reported symptoms for esophageal cancer patients undergoing curative intent treatment Vaibhav Gupta, MD, Catherine Allen-Ayodabo, MD, MPH, Laura Davis, MSc, Haoyu Zhao, MPH, Julie Hallet, MD MSc, Alyson L. Mahar, PhD, Jolie Ringash, MD, MSc, Biniam Kidane, MD, MSc, Gail Darling, MD, Natalie G. Coburn, MD, MPH PII:
S0003-4975(19)31417-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.08.030
Reference:
ATS 33052
To appear in:
The Annals of Thoracic Surgery
Received Date: 6 February 2019 Revised Date:
8 July 2019
Accepted Date: 8 August 2019
Please cite this article as: Gupta V, Allen-Ayodabo C, Davis L, Zhao H, Hallet J, Mahar AL, Ringash J, Kidane B, Darling G, Coburn NG, Patient-reported symptoms for esophageal cancer patients undergoing curative intent treatment, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/ j.athoracsur.2019.08.030. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
June 2019 Patient-reported symptoms for esophageal cancer patients undergoing curative intent treatment Running head: Patient symptoms in esophageal cancer Vaibhav Gupta MD1,2, Catherine Allen-Ayodabo MD, MPH3, Laura Davis MSc3, Haoyu Zhao MPH4, Julie Hallet MD MSc1,2,3,4, Alyson L. Mahar PhD5, Jolie Ringash MD, MSc2,6, Biniam Kidane MD, MSc7, Gail Darling MD2,8, Natalie G. Coburn MD, MPH1,2,3,4 1. 2. 3. 4. 5.
Division of General Surgery, Department of Surgery, University of Toronto, Canada. Institute of Health Policy, Management, and Evaluation, University of Toronto, Canada. Evaluative Clinical Sciences, Sunnybrook Research Institute, Toronto, Canada. Institute for Clinical Evaluative Sciences, Toronto, Canada. Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Canada. 6. Department of Radiation Oncology, University of Toronto, Canada. 7. Section of Thoracic Surgery, Department of Surgery, University of Manitoba, Canada. 8. Division of Thoracic Surgery, Department of Surgery, University of Toronto, Canada.
Presented at: Society of Thoracic Surgeons Annual Meeting, San Diego, CA, January 27-29, 2019 (Poster) Word count: 4569 Corresponding Author: Dr. Natalie G. Coburn Sunnybrook Health Sciences Centre T2-11, 2075 Bayview Avenue Toronto, ON M4N 3M5 Canada [email protected]
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Abstract (238 words) Background: Esophageal cancer (EC) patients experience considerable symptom burden from treatment. This study utilized population-level patient-reported Edmonton Symptom Assessment System (ESAS) scores collected as part of standard clinical care to describe symptom trajectories and characteristics associated with severe symptoms for patients undergoing curative intent EC treatment. Methods: EC patients treated with curative intent at regional cancer centers and affiliates between 2009-2016 and assessed for symptoms in the 12 months following diagnosis were included. ESAS measures nine common patient-reported cancer symptoms. The outcome was reporting of severe (≥7/10) symptom scores. Multivariable analyses were used to identify characteristics associated with severe symptom scores. Results: 1,751 patients reported a median of 7 (IQR 4-12) ESAS assessments in the year following diagnosis, for a total of 14,953 unique ESAS assessments included in the analysis. The most frequently reported severe symptoms were lack of appetite (n=918, 52%), tiredness (n=787, 45%) and poor wellbeing (713, 40.7%). The highest symptom burden is within the first five months following diagnosis, with moderate improvement in symptom burden in the second half of the first year. Characteristics associated with severe scores for all symptoms included female sex, high comorbidity, lower socioeconomic status, urban residence, and symptom assessment temporally close to diagnosis. Conclusions: This study demonstrates a high symptom burden for EC patients undergoing curative intent therapy. Targeted treatment of common severe symptoms, and increased support for patients at risk for severe symptoms, may enhance patient quality of life.
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Esophageal cancer patients experience a high degree of morbidity. Most patients are symptomatic at presentation. Patients who are eligible for curative intent therapy undergo combinations of chemotherapy, radiotherapy, and surgery, with the potential for treatmentrelated complications. These multi-modal treatments also often affect quality of life (QoL), with patients highly symptomatic due to a combination of disease- and treatment-related factors.(1) Understanding the symptoms esophageal cancer patients experience and which patients are at risk of experiencing severe symptoms is a key priority in developing solutions to improve QoL. Cancer Care Ontario (CCO) oversees cancer care delivery in Canada’s most populous province. In 2007, CCO implemented opportunistic collection of patient-reported symptom scores for any patient attending a regional cancer center or affiliate as part of routine clinical care. Studying patient-reported symptom scores collected on a population level presents a valuable opportunity to examine esophageal cancer symptoms as patients undergo therapy, and to identify characteristics associated with severe symptoms. This line of inquiry is an important first step to understanding the burden of severe symptoms and identifying potential ways to improve patient QoL. The objective of this study was to answer two questions: among patients undergoing curative intent treatment for esophageal cancer, 1) what are the symptom trajectories in the 12 months
following
diagnosis
for
all
patients
and
those
undergoing
neoadjuvant
chemoradiotherapy and surgery, and 2) what characteristics are associated with severe symptoms?
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Patients and Methods Study Setting, Design, and Population This study used administrative data collected through patient interactions with the universal, single-payer health system in Ontario (population 14.2 million in 2017), made available for research purposes through ICES. Ethics approval for this study was obtained from the Sunnybrook Health Sciences Centre Research Ethics Board and we adhered to the data confidentiality and privacy policies of ICES. We performed a retrospective, population-based cohort study including adults diagnosed with esophageal and gastroesophageal junction cancer (ICD-O-3 codes C15.0-C15.9 and C16.0) from January 2009 to September 2016 identified in the Ontario Cancer Registry (OCR). The following exclusion criteria were applied: missing unique identifier, more than one cancer diagnosis at any time, death before diagnosis, did not die and less than 6 months follow-up after diagnosis, no contact with a cancer center or affiliate, not receiving curative treatment, and not eligible for government health insurance. Curative treatment was defined, post hoc, as having received surgery alone, chemoradiotherapy alone, surgery and chemotherapy, or surgery and chemoradiotherapy by the end of the first year following diagnosis. Data Sources Linked administrative datasets (details in Supplemental eTable 1) were used to capture patient characteristics, symptom scores and covariates: Ontario Cancer Registry, Ontario Health Insurance Plan Database, Symptom Management Reporting Database, Canadian Institute for Health Information Discharge Abstract Database, Cancer Activity Level Reporting, Registered Persons Database, National Ambulatory Care Reporting System, Permanent Resident Database
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of Citizenship and Immigration Canada, Ontario Marginalization Index, and 2006 Canadian Census. These have been described in detail previously.(2) Primary Outcome The primary outcome was report of a severe symptom score in each of the 12 months following diagnosis.
These symptom scores are reported by patients prospectively on an
electronic kiosk when they check into a cancer center for an outpatient visit, given to clinicians during the visit, and the data are available through the Symptom Management Reporting Database. If patients reported multiple scores in one month, the highest was retained. Patientreported symptoms were measured using the Edmonton Symptom Assessment Scale (ESAS), which is a validated and reliable tool measuring nine common cancer-associated symptoms (Supplemental eFigure1): anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and overall wellbeing.(3, 4) It was initially developed in 1991 in a palliative care population and was then modified to measure symptoms in the cancer population.(5, 6) It has been validated in inpatients and outpatients, in a variety of disease sites, around the world, and is now used across Canada and internationally for clinical care and research.(3, 7, 8) On an 11-point scale where 0 is “no symptoms” and 10 is “worst possible symptom severity”, a score ≥7 is considered severe and correlates with high symptom burden, functional impairment, and poor quality-of life in patients with cancer.(9, 10) Variables We identified and studied patient characteristics that may be associated with patients’ symptom scores a priori based on clinical significance: age, sex, diagnosis year, months from diagnosis, comorbidity (low or high), urban residence (yes/no), immigration status (immigrant or non-immigrant), deprivation quintile (1 to 5 from least to most deprived), and treatment modality
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(surgery alone, chemoradiotherapy alone, surgery and chemotherapy, or surgery and chemoradiotherapy). Variable definitions are available in the Supplemental Methods and Supplemental eTable2. Statistical Analysis Baseline characteristics were described with frequencies and proportions. Patients with ESAS assessments were compared to patients without ESAS assessments using means, proportions, and the two-sample t-test or chi-squared test to assess for generalizability. Similarly, patients were compared by number of ESAS assessments completed. Line graphs were created to describe the proportion of patients reporting severe symptoms by month from diagnosis, out of all patients completing a symptom assessment that month. The line graphs were plotted for two groups: all patients, and the subgroup receiving neoadjuvant chemoradiotherapy and surgery to show the relationship between these therapies and symptoms. Trendlines do not to represent continuous data, but were included to facilitate the visualization of trends over time by symptom. Characteristics associated with severe scores for each symptom were explored using multivariable modified Poisson regression models with robust error variance.(11) Generalized estimating equations with exchangeable correlation structures were used to account for repeated measures from each patient. All variables were kept in the model. Results were considered statistically significant if p<0.05. All analyses were performed using SAS Enterprise Guide, version 7.1 (SAS Institute, Cary, NC).
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Results Baseline Characteristics Of 2,011 patients meeting study criteria (Figure 1), 1,751 patients (87%) were screened for symptoms in the year following diagnosis and included in the analysis. In the most recent years, more than 93% of all patients were screened for symptoms. Patients not screened for symptoms tended to appear earlier in the study period, be slightly older, have more comorbidities, live in a major urban setting, or be treated with surgery alone (Table 1). Among patients screened for symptoms, characteristics associated with completing more assessments included younger age, fewer comorbidities, diagnosis later in the study period, higher socioeconomic status, and treatment with multimodal therapy (Supplemental eTable 3). Included patients contributed a median of 7 ESAS assessments (IQR 4-12), for a total of 14,953 unique ESAS assessments included in the analysis. Median survival was 20 months (IQR 11-39). Overall Proportion of Patients Reporting Severe Symptoms The proportion of patients reporting at least one severe score for each symptom during the study period is presented in Table 2 . The most frequently reported severe symptoms at any time during the first 12 months after diagnosis were lack of appetite (n=918, 52%), tiredness (n=787, 45%) and poor wellbeing (n=713, 40.7%). Over 20% of patients reported severe depression and over 25% reported severe anxiety over the observation period. Proportion of Patients Reporting Severe Symptoms by Month Figure 2 plots the proportion of patients reporting severe symptoms by month in the 12 months following diagnosis. The highest symptom burden is within the first five months following diagnosis, with moderate improvement in symptom burden in the second half of the first year. At month 12, approximately 15% of patients reported severe lack of appetite, 15%
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reported severe tiredness, and 12% reported severe poor wellbeing. In the subgroup undergoing neoadjuvant
chemoradiotherapy
and
surgery,
the
median
start
and
end
time
of
chemoradiotherapy is marked in Figure 3. Characteristics Associated with Severe Symptoms Characteristics associated with severe scores for all symptoms included female sex, high comorbidity, lower socioeconomic status (greatest deprivation), urban residence, and symptom assessment temporally close to diagnosis. Table 3 shows factors associated with severe lack of appetite, tiredness, and poor wellbeing (the most prevalent severe symptoms). Supplemental eTable 4 and Supplemental eTable 5 show factors associated with other severe physical and psychological symptoms, respectively. Of note, lack of appetite was the only symptom that had an association with diagnosis year; the risk of reporting severe lack of appetite decreased over the years of the study. Other symptoms did not improve or worsen over the eight-year study period. Increasing age was associated with increased risk of reporting severe lack of appetite and nausea. Treatment modality was not associated with report of severe symptoms, except that patients receiving chemoradiotherapy alone anytime during the study period were more likely to report severe pain and poor wellbeing; this effect was likely driven by the high proportion of patients reporting severe scores during and immediately following the treatment phase.
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Comment We performed a population-based study of 14,953 prospective, patient-reported symptom score assessments reported by 1,751 esophageal cancer patients over one year following diagnosis. Its generalizability is strengthened by the fact that symptom assessments were completed in the real world across sixteen cancer centers & multiple affiliates, and most eligible patients (87%) completed symptom assessments. We uncovered four important findings. First, patients undergoing curative intent therapy experience high symptom burden, which is worst in the first five months after diagnosis. Second, a considerable proportion of patients continue to experience severe symptoms even one year following diagnosis. Third, lack of appetite is the most prevalent severe symptom. Fourth, characteristics associated with severe scores vary by symptom, but characteristics common to all symptoms include female sex, high comorbidity, lower socioeconomic status, urban residence, and the first five months following diagnosis. Comprehensive assessments of patient-reported symptoms for esophageal cancer are lacking.(12, 13) Previous investigations of patient-reported outcomes have focused on questions such as the association of patient symptoms with cancer stage,(14) QoL outcomes following therapy at discrete time points,(15, 16) and especially on the prognostic value of QoL scores.(1720) A few, small studies have looked at changes in patient symptoms or QoL during therapy and over time.(16, 21, 22) Our study is an important addition to the literature as it is the first detailed analysis of patient-reported symptoms throughout the first year following diagnosis, using multicenter, prospectively-collected data in a large population of esophageal cancer patients. Our group previously examined symptom burden in the year following diagnosis for 120,745 patients with oropharyngeal, gastrointestinal, respiratory, breast, gynecologic, genitourinary, nervous system and orbit, and hematopoietic/lymphatic cancers surviving one
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year.(2) There were similarities in the characteristics associated with report of severe symptoms in the esophageal cancer population compared to the general cancer population: female sex, high comorbidity, lower socioeconomic status, urban residence, and symptom assessment in the immediate post-diagnosis period. While for all cancers, younger age was associated with increased symptom burden, in the esophageal cancer population, we found older age increased the risk of reporting severe lack of appetite and nausea. Supportive care interventions can focus on subgroups at risk of experiencing greater symptom burden. Lack of appetite appears to be a particularly challenging symptom for the esophageal cancer patient population; it was the most frequently-reported severe symptom, with 52% of patients having a score ≥7 at least once in the study period. We recognize that there are limited treatments for lack of appetite, but addressing issues that contribute to it may help. Esophageal cancer symptoms such as dysphagia, regurgitation, coughing, chest pain, or heartburn may cause patients to lose their appetite. Further, chemotherapy, radiotherapy, surgery, pain, tiredness, or depression can all individually exacerbate appetite loss. Lack of appetite should be carefully tracked and treated proactively, including assessment and management of its causes; clinical dieticians can provide support through nutritional strategies.(23) The burden of mental health symptoms we found in this study is significant, with 20% and 25% of patients reporting scores ≥7 for depression and anxiety, respectively. An ESAS screening score greater than two in depression is clinically meaningful and these patients should be referred for additional assessment and support.(24, 25) Clearly, a depression score ≥7 is truly concerning. Our results highlight the value of screening for mental health symptoms in esophageal cancer patients. Next steps in this research program include investigating what, if any, action is taken when a high depression score is reported.
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These findings are an important call-to-action for policymakers and providers to prioritize addressing patient symptoms during esophageal cancer treatment. There is evidence from a large randomized trial at Memorial Sloan Kettering Cancer Center that measuring symptoms and intervening decreases costs, benefits patient QoL, and improves survival.(26, 27) Symptom screening can inform hospitals and health systems in designing supportive care because it provides background data and understanding of what symptoms patients experience and which populations are vulnerable to high symptom burden. Symptom screening may also uncover treatment-related toxicities, psychosocial barriers and functional limitations, which can delay or limit adherence to therapy. Three methodological characteristics or limitations affect the reporting of severe symptoms in our study. First, only patients attending outpatient cancer center visits complete a symptom assessment. Patients admitted to inpatient units would be expected to have worse symptoms. Second, ESAS measurement was opportunistic, not at specified time intervals; as a result, there can be reporting bias such as only completing a symptom assessment when a patient is well enough to attend the cancer center. Third, patients had varying follow-up time if they died within one year following diagnosis, and it may be patients with the most severe scores who died. Therefore, the study may under-estimate the prevalence of severe symptoms, reinforcing the finding that symptom burden is high. Another implication of patients dying during the study period is that symptoms may not truly be improving over the course of 12 months. In conclusion, this comprehensive population-based analysis of prospective patientreported symptom scores demonstrates a high symptom burden for esophageal patients undergoing curative intent therapy. These results outline the need for better targeted treatment of common severe symptoms, and increased support for more vulnerable patients at risk for severe
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symptoms, to improve patient-centered supportive care. This information can inform and support early and ongoing symptom assessment and management warranted to improve patient-centered care and potentially quality of life in esophageal cancer patients.
Acknowledgment: This study is supported by the Sherif and MaryLou Hanna Chair in Surgical Oncology Research at Sunnybrook Health Sciences Centre. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and LongTerm Care (MOHLTC). Parts of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI) and by Cancer Care Ontario (CCO). The analyses, opinions, results and conclusions reported in this paper are those of the authors and are independent from ICES, MOHLTC, CIHI, and CCO. No endorsement by any of these organizations is intended or should be inferred.
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References 1. Darling GE. Quality of life in patients with esophageal cancer. Thorac Surg Clin 2013;23(4):569-575. 2. Bubis LD, Davis L, Mahar A et al. Symptom burden in the first year after cancer diagnosis: An analysis of patient-reported outcomes. J Clin Oncol 2018:JCO2017760876. 3. Nekolaichuk C, Watanabe S, Beaumont C. The edmonton symptom assessment system: A 15-year retrospective review of validation studies (1991--2006). Palliat Med 2008;22(2):111122. 4. Richardson LA, Jones GW. A review of the reliability and validity of the edmonton symptom assessment system. Curr Oncol 2009;16(1):55. 5. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The edmonton symptom assessment system (esas): A simple method for the assessment of palliative care patients. J Palliat Care 1991;7(2):6-9. 6. Watanabe SM, Nekolaichuk C, Beaumont C, Johnson L, Myers J, Strasser F. A multicenter study comparing two numerical versions of the edmonton symptom assessment system in palliative care patients. J Pain Symptom Manage 2011;41(2):456-468. 7. Tran K, Zomer S, Chadder J et al. Measuring patient-reported outcomes to improve cancer care in canada: An analysis of provincial survey data. Curr Oncol 2018;25(2):176-179. 8. Hui D, Shamieh O, Paiva CE et al. Minimal clinically important differences in the edmonton symptom assessment scale in cancer patients: A prospective, multicenter study. Cancer 2015;121(17):3027-3035. 9. Selby D, Cascella A, Gardiner K et al. A single set of numerical cutpoints to define moderate and severe symptoms for the edmonton symptom assessment system. J Pain Symptom Manage 2010;39(2):241-249. 10. Selby D, Chakraborty A, Myers J, Saskin R, Mazzotta P, Gill A. High scores on the edmonton symptom assessment scale identify patients with self-defined high symptom burden. J Palliat Med 2011;14(12):1309-1316. 11. Yelland LN, Salter AB, Ryan P. Performance of the modified poisson regression approach for estimating relative risks from clustered prospective data. Am J Epidemiol 2011;174(8):984-992. 12. Jacobs M, Macefield RC, Blazeby JM et al. Systematic review reveals limitations of studies evaluating health-related quality of life after potentially curative treatment for esophageal cancer. Qual Life Res 2013;22(7):1787-1803. 13. Parameswaran R, McNair A, Avery KN et al. The role of health-related quality of life outcomes in clinical decision making in surgery for esophageal cancer: A systematic review. Ann Surg Oncol 2008;15(9):2372-2379. 14. Kidane B, Ali A, Sulman J, Wong R, Knox JJ, Darling GE. Health-related quality of life measure distinguishes between low and high clinical t stages in esophageal cancer. Ann Transl Med 2018;6(13):270. 15. Noordman BJ, Verdam MGE, Lagarde SM et al. Effect of neoadjuvant chemoradiotherapy on health-related quality of life in esophageal or junctional cancer: Results from the randomized cross trial. J Clin Oncol 2017:JCO2017737718. 16. Safieddine N, Xu W, Quadri SM et al. Health-related quality of life in esophageal cancer: Effect of neoadjuvant chemoradiotherapy followed by surgical intervention. J Thorac Cardiovasc Surg 2009;137(1):36-42.
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17. Kidane B, Sulman J, Xu W et al. Baseline measure of health-related quality of life (functional assessment of cancer therapy-esophagus) is associated with overall survival in patients with esophageal cancer. J Thorac Cardiovasc Surg 2016;151(6):1571-1580. 18. Djarv T, Lagergren P. Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery. Eur J Cancer 2011;47(4):530-535. 19. Djarv T, Metcalfe C, Avery KN, Lagergren P, Blazeby JM. Prognostic value of changes in health-related quality of life scores during curative treatment for esophagogastric cancer. J Clin Oncol 2010;28(10):1666-1670. 20. Quinten C, Martinelli F, Coens C et al. A global analysis of multitrial data investigating quality of life and symptoms as prognostic factors for survival in different tumor sites. Cancer 2014;120(2):302-311. 21. Blazeby JM, Farndon JR, Donovan J, Alderson D. A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma. Cancer 2000;88(8):17811787. 22. Trudel JG, Sulman J, Atenafu EG, Kidane B, Darling GE. Longitudinal evaluation of trial outcome index scores in patients with esophageal cancer. Ann Thorac Surg 2016;102(1):269275. 23. Arends J, Bachmann P, Baracos V et al. Espen guidelines on nutrition in cancer patients. Clin Nutr 2017;36(1):11-48. 24. Bagha SM, Macedo A, Jacks LM et al. The utility of the edmonton symptom assessment system in screening for anxiety and depression. Eur J Cancer Care (Engl) 2013;22(1):60-69. 25. Ripamonti CI, Bandieri E, Pessi MA, Maruelli A, Buonaccorso L, Miccinesi G. The edmonton symptom assessment system (esas) as a screening tool for depression and anxiety in non-advanced patients with solid or haematological malignancies on cure or follow-up. Support Care Cancer 2014;22(3):783-793. 26. Basch E, Deal AM, Kris MG et al. Symptom monitoring with patient-reported outcomes during routine cancer treatment: A randomized controlled trial. J Clin Oncol 2016;34(6):557565. 27. Basch E, Deal AM, Dueck AC et al. Overall survival results of a trial assessing patientreported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017;318(2):197-198.
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Table 1: Characteristics of patients receiving symptom screening; n=1751, 87% (row percent). No Symptom Screening Symptom Screening (excluded, n=260) (included, n=1,751)
Variable
p-value
2009
72 (30.6%)
163 (69.4%)
2010
49 (22.1%)
173 (77.9%)
2011
29 (12.3%)
207 (87.7%)
2012
16 (6.4%)
233 (93.6%)
2013
28 (10.3%)
245 (89.7%)
2014
33 (11.8%)
246 (88.2%)
2015
19 (6.6%)
267 (93.4%)
2016
14 (6.1%)
217 (93.9%)
65.67 ± 10.83
63.38 ± 10.58
0.001
Female
64 (15.1%)
360 (84.9%)
0.14
Male
196 (12.4%)
1,391 (87.6%)
Low
193 (12.1%)
1403 (87.9%)
High
67 (16.1%)
348 (83.9%)
Major urban
247 (13.5%)
1,584 (86.5%)
Rural
11 (7.1%)
143 (92.9%)
(lowest)1
36 (9.3%)
352 (90.7%)
2
33 (8.1%)
372 (91.9%)
3
61 (15.2%)
341 (84.8%)
4
66 (16.8%)
328 (83.2%)
(highest) 5
62 (15.1%)
348 (84.9%)
Residency Status
Non-immigrant
239 (12.8%)
1,634 (87.2%)
Immigrant
21 (15.2%)
117 (84.8%)
Treatment
CRT
43 (6.4%)
632 (93.6%)
117 (31.9%)
250 (68.1%)
CRT & Surgery
59 (8.2%)
661 (91.8%)
Chemotherapy & Surgery
41 (16.5%)
208 (83.5%)
Diagnosis year
Age (mean ± SD) Sex
Comorbidity
Rurality
Deprivation Quintile
Surgery only
<0.001
0.01
<0.001
<0.001
0.61
<0.001
CRT = chemoradiotherapy.
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Table 2: Number of patients reporting any severe symptom at least once during the study period. Symptom
Number of patients (%)
Lack of Appetite
918 (52.4%)
Tiredness
787 (45.0%)
Poor Wellbeing
713 (40.7%)
Drowsiness
536 (30.6%)
Anxiety
463 (26.4%)
Pain
447 (25.5%)
Nausea
425 (24.3%)
Depression
359 (20.5%)
Shortness of breath
345 (19.7%)
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June 2019 Table 3: Multivariable analysis for characteristics associated with severe lack of appetite, tiredness, and poor wellbeing. Covariate Sex Age
Lack of Appetite Male Female <50 50-59 60-69
70-79 ≥80 Immigration Non-immigrants status Immigrants Rural Rurality Index Urban Deprivation quintile
Diagnosis year
(highest) 5 (lowest) 1 2 3 4 2009 2010 2011 2012 2013 2014 2015 2016
Tiredness
Poor Wellbeing
RR Reference 1.19 Reference
LCL UCL pvalue
RR
LCL UCL
pvalue
RR
LCL UCL
pvalue
1.05
1.34
0.01
1.25
1.08
1.44
0.003
1.32
1.13
1.55
<.001
1.31 1.34 1.33 1.43 Reference 0.85
1.04 1.08 1.05 1.04
1.63 1.67 1.67 1.95
0.02 0.01 0.02 0.03
1.05 1.09 1.16 1.03
0.82 0.86 0.90 0.73
1.35 1.38 1.49 1.46
0.67 0.48 0.26 0.86
1.12 1.14 1.24 1.07
0.84 0.87 0.93 0.72
1.48 1.50 1.66 1.60
0.44 0.35 0.15 0.73
0.67
1.08
0.17
0.96
0.75
1.23
0.77
0.92
0.69
1.22
0.54
Reference 0.96 Reference
0.81
1.14
0.65
1.19
0.95
1.49
0.13
1.10
0.87
1.40
0.41
0.79 0.90 0.85
0.66 0.77 0.72
0.94 1.06 1.01
0.01 0.21 0.07
0.68 0.87 0.89
0.55 0.72 0.73
0.85 1.04 1.09
0.001 0.13 0.27
0.66 0.85 0.97
0.52 0.70 0.79
0.84 1.05 1.19
<.001 0.13 0.74
0.87 Reference
0.73
1.03
0.11
0.99
0.81
1.20
0.89
0.94
0.76
1.17
0.60
0.75 0.91
0.59 0.74
0.95 1.12
0.02 0.38
0.79 0.70
0.64 0.56
0.97 0.88
0.02 0.002
1.06 1.05 1.00 1.01
0.80 0.80 0.77 0.78
1.39 1.38 1.30 1.32
0.69 0.71 0.99 0.92
0.93 1.06 1.17 0.99
0.68 0.79 0.88 0.74
1.26 1.43 1.54 1.33
0.64 0.68 0.28 0.93
0.61 0.69 0.65
0.49 0.55 0.52
0.77 0.85 0.82
<.001 <.001 <.001
0.85 1.09 1.00
0.65 0.84 0.76
1.12 1.40 1.30
0.26 0.52 0.99
0.83 0.98 0.89
0.62 0.75 0.66
1.12 1.29 1.20
0.22 0.90 0.45
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Patient Symptoms in Esophageal Cancer Comorbidity
Low High Surgery only
June 2019
Reference 1.14 Reference 1.12 1.01
1.00
1.31
0.06
1.34
1.16
1.56
<.001
1.21
1.02
1.42
0.03
CRT 0.93 1.35 0.25 1.19 CRT & Surgery 0.83 1.23 0.91 0.91 Chemo & 0.87 0.68 1.11 0.27 0.94 Surgery 1 Reference Month from diagnosis 2 1.23 1.06 1.43 0.01 1.31 3 1.22 1.04 1.42 0.01 1.64 4 1.12 0.94 1.32 0.20 1.46 5 1.09 0.91 1.30 0.34 1.37 6 0.93 0.76 1.13 0.46 1.18 7 1.00 0.83 1.21 0.97 1.24 8 0.95 0.77 1.16 0.60 1.26 9 0.81 0.65 1.01 0.06 1.05 10 1.10 0.75 0.58 0.97 0.03 11 0.91 0.64 0.49 0.84 0.001 12 1.21 0.81 0.64 1.04 0.10 RR = relative risk. LCL = lower confidence limit. UCL = upper confidence limit.
0.95 0.72
1.48 1.14
0.13 0.40
1.35 1.04
1.05 0.80
1.75 1.35
0.02 0.77
0.71
1.24
0.67
1.04
0.76
1.42
0.81
1.10 1.37 1.20 1.12 0.95 0.99 1.00 0.82 0.85 0.68 0.95
1.57 1.97 1.77 1.67 1.47 1.54 1.58 1.35 1.41 1.22 1.55
0.003 <.001 <.001 0.002 0.14 0.06 0.05 0.71 0.46 0.54 0.12
1.17 1.25 1.13 1.10 0.93 1.06 0.99 0.78 1.10 0.92 0.97
0.95 1.01 0.91 0.87 0.71 0.82 0.76 0.57 0.83 0.69 0.73
1.45 1.54 1.42 1.40 1.21 1.36 1.29 1.06 1.45 1.24 1.30
0.14 0.04 0.27 0.42 0.58 0.65 0.94 0.11 0.52 0.60 0.85
Treatment modality
18
June 2019 Figure Legends
Figure 1: Cohort diagram. RCC = regional cancer center. Figure 2: Proportion of patients reporting severe symptom scores by month of assessment in the first year following diagnosis. Trendlines do not to represent continuous data. Figure 3: Proportion of patients treated with preoperative chemoradiotherapy and surgery reporting severe symptom scores by month of assessment in the first year following diagnosis. Trendlines do not to represent continuous data.
22
June 2019 Supplemental Material
eTable 1: Data sources for the study eTable 2: Definitions for receipt of treatment eTable 3: Characteristics of patients by number of symptom screening assessments completed; n=1751 (row percent). eTable 4: Multivariable analysis for characteristics associated with severe nausea, pain, and shortness of breath eTable 5: Multivariable analysis for characteristics associated with severe anxiety, depression, and drowsiness eFigure 1: Cancer Care Ontario ESAS form Supplemental Methods: Variable definitions.
23
S0003-4975(19)31417-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.08.030
Reference:
ATS 33052
To appear in:
The Annals of Thoracic Surgery
Received Date: 6 February 2019 Revised Date:
8 July 2019
Accepted Date: 8 August 2019
Please cite this article as: Gupta V, Allen-Ayodabo C, Davis L, Zhao H, Hallet J, Mahar AL, Ringash J, Kidane B, Darling G, Coburn NG, Patient-reported symptoms for esophageal cancer patients undergoing curative intent treatment, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/ j.athoracsur.2019.08.030. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
June 2019 Patient-reported symptoms for esophageal cancer patients undergoing curative intent treatment Running head: Patient symptoms in esophageal cancer Vaibhav Gupta MD1,2, Catherine Allen-Ayodabo MD, MPH3, Laura Davis MSc3, Haoyu Zhao MPH4, Julie Hallet MD MSc1,2,3,4, Alyson L. Mahar PhD5, Jolie Ringash MD, MSc2,6, Biniam Kidane MD, MSc7, Gail Darling MD2,8, Natalie G. Coburn MD, MPH1,2,3,4 1. 2. 3. 4. 5.
Division of General Surgery, Department of Surgery, University of Toronto, Canada. Institute of Health Policy, Management, and Evaluation, University of Toronto, Canada. Evaluative Clinical Sciences, Sunnybrook Research Institute, Toronto, Canada. Institute for Clinical Evaluative Sciences, Toronto, Canada. Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Canada. 6. Department of Radiation Oncology, University of Toronto, Canada. 7. Section of Thoracic Surgery, Department of Surgery, University of Manitoba, Canada. 8. Division of Thoracic Surgery, Department of Surgery, University of Toronto, Canada.
Presented at: Society of Thoracic Surgeons Annual Meeting, San Diego, CA, January 27-29, 2019 (Poster) Word count: 4569 Corresponding Author: Dr. Natalie G. Coburn Sunnybrook Health Sciences Centre T2-11, 2075 Bayview Avenue Toronto, ON M4N 3M5 Canada [email protected]
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Patient Symptoms in Esophageal Cancer
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Abstract (238 words) Background: Esophageal cancer (EC) patients experience considerable symptom burden from treatment. This study utilized population-level patient-reported Edmonton Symptom Assessment System (ESAS) scores collected as part of standard clinical care to describe symptom trajectories and characteristics associated with severe symptoms for patients undergoing curative intent EC treatment. Methods: EC patients treated with curative intent at regional cancer centers and affiliates between 2009-2016 and assessed for symptoms in the 12 months following diagnosis were included. ESAS measures nine common patient-reported cancer symptoms. The outcome was reporting of severe (≥7/10) symptom scores. Multivariable analyses were used to identify characteristics associated with severe symptom scores. Results: 1,751 patients reported a median of 7 (IQR 4-12) ESAS assessments in the year following diagnosis, for a total of 14,953 unique ESAS assessments included in the analysis. The most frequently reported severe symptoms were lack of appetite (n=918, 52%), tiredness (n=787, 45%) and poor wellbeing (713, 40.7%). The highest symptom burden is within the first five months following diagnosis, with moderate improvement in symptom burden in the second half of the first year. Characteristics associated with severe scores for all symptoms included female sex, high comorbidity, lower socioeconomic status, urban residence, and symptom assessment temporally close to diagnosis. Conclusions: This study demonstrates a high symptom burden for EC patients undergoing curative intent therapy. Targeted treatment of common severe symptoms, and increased support for patients at risk for severe symptoms, may enhance patient quality of life.
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Patient Symptoms in Esophageal Cancer
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Esophageal cancer patients experience a high degree of morbidity. Most patients are symptomatic at presentation. Patients who are eligible for curative intent therapy undergo combinations of chemotherapy, radiotherapy, and surgery, with the potential for treatmentrelated complications. These multi-modal treatments also often affect quality of life (QoL), with patients highly symptomatic due to a combination of disease- and treatment-related factors.(1) Understanding the symptoms esophageal cancer patients experience and which patients are at risk of experiencing severe symptoms is a key priority in developing solutions to improve QoL. Cancer Care Ontario (CCO) oversees cancer care delivery in Canada’s most populous province. In 2007, CCO implemented opportunistic collection of patient-reported symptom scores for any patient attending a regional cancer center or affiliate as part of routine clinical care. Studying patient-reported symptom scores collected on a population level presents a valuable opportunity to examine esophageal cancer symptoms as patients undergo therapy, and to identify characteristics associated with severe symptoms. This line of inquiry is an important first step to understanding the burden of severe symptoms and identifying potential ways to improve patient QoL. The objective of this study was to answer two questions: among patients undergoing curative intent treatment for esophageal cancer, 1) what are the symptom trajectories in the 12 months
following
diagnosis
for
all
patients
and
those
undergoing
neoadjuvant
chemoradiotherapy and surgery, and 2) what characteristics are associated with severe symptoms?
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Patient Symptoms in Esophageal Cancer
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Patients and Methods Study Setting, Design, and Population This study used administrative data collected through patient interactions with the universal, single-payer health system in Ontario (population 14.2 million in 2017), made available for research purposes through ICES. Ethics approval for this study was obtained from the Sunnybrook Health Sciences Centre Research Ethics Board and we adhered to the data confidentiality and privacy policies of ICES. We performed a retrospective, population-based cohort study including adults diagnosed with esophageal and gastroesophageal junction cancer (ICD-O-3 codes C15.0-C15.9 and C16.0) from January 2009 to September 2016 identified in the Ontario Cancer Registry (OCR). The following exclusion criteria were applied: missing unique identifier, more than one cancer diagnosis at any time, death before diagnosis, did not die and less than 6 months follow-up after diagnosis, no contact with a cancer center or affiliate, not receiving curative treatment, and not eligible for government health insurance. Curative treatment was defined, post hoc, as having received surgery alone, chemoradiotherapy alone, surgery and chemotherapy, or surgery and chemoradiotherapy by the end of the first year following diagnosis. Data Sources Linked administrative datasets (details in Supplemental eTable 1) were used to capture patient characteristics, symptom scores and covariates: Ontario Cancer Registry, Ontario Health Insurance Plan Database, Symptom Management Reporting Database, Canadian Institute for Health Information Discharge Abstract Database, Cancer Activity Level Reporting, Registered Persons Database, National Ambulatory Care Reporting System, Permanent Resident Database
4
Patient Symptoms in Esophageal Cancer
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of Citizenship and Immigration Canada, Ontario Marginalization Index, and 2006 Canadian Census. These have been described in detail previously.(2) Primary Outcome The primary outcome was report of a severe symptom score in each of the 12 months following diagnosis.
These symptom scores are reported by patients prospectively on an
electronic kiosk when they check into a cancer center for an outpatient visit, given to clinicians during the visit, and the data are available through the Symptom Management Reporting Database. If patients reported multiple scores in one month, the highest was retained. Patientreported symptoms were measured using the Edmonton Symptom Assessment Scale (ESAS), which is a validated and reliable tool measuring nine common cancer-associated symptoms (Supplemental eFigure1): anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and overall wellbeing.(3, 4) It was initially developed in 1991 in a palliative care population and was then modified to measure symptoms in the cancer population.(5, 6) It has been validated in inpatients and outpatients, in a variety of disease sites, around the world, and is now used across Canada and internationally for clinical care and research.(3, 7, 8) On an 11-point scale where 0 is “no symptoms” and 10 is “worst possible symptom severity”, a score ≥7 is considered severe and correlates with high symptom burden, functional impairment, and poor quality-of life in patients with cancer.(9, 10) Variables We identified and studied patient characteristics that may be associated with patients’ symptom scores a priori based on clinical significance: age, sex, diagnosis year, months from diagnosis, comorbidity (low or high), urban residence (yes/no), immigration status (immigrant or non-immigrant), deprivation quintile (1 to 5 from least to most deprived), and treatment modality
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Patient Symptoms in Esophageal Cancer
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(surgery alone, chemoradiotherapy alone, surgery and chemotherapy, or surgery and chemoradiotherapy). Variable definitions are available in the Supplemental Methods and Supplemental eTable2. Statistical Analysis Baseline characteristics were described with frequencies and proportions. Patients with ESAS assessments were compared to patients without ESAS assessments using means, proportions, and the two-sample t-test or chi-squared test to assess for generalizability. Similarly, patients were compared by number of ESAS assessments completed. Line graphs were created to describe the proportion of patients reporting severe symptoms by month from diagnosis, out of all patients completing a symptom assessment that month. The line graphs were plotted for two groups: all patients, and the subgroup receiving neoadjuvant chemoradiotherapy and surgery to show the relationship between these therapies and symptoms. Trendlines do not to represent continuous data, but were included to facilitate the visualization of trends over time by symptom. Characteristics associated with severe scores for each symptom were explored using multivariable modified Poisson regression models with robust error variance.(11) Generalized estimating equations with exchangeable correlation structures were used to account for repeated measures from each patient. All variables were kept in the model. Results were considered statistically significant if p<0.05. All analyses were performed using SAS Enterprise Guide, version 7.1 (SAS Institute, Cary, NC).
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Patient Symptoms in Esophageal Cancer
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Results Baseline Characteristics Of 2,011 patients meeting study criteria (Figure 1), 1,751 patients (87%) were screened for symptoms in the year following diagnosis and included in the analysis. In the most recent years, more than 93% of all patients were screened for symptoms. Patients not screened for symptoms tended to appear earlier in the study period, be slightly older, have more comorbidities, live in a major urban setting, or be treated with surgery alone (Table 1). Among patients screened for symptoms, characteristics associated with completing more assessments included younger age, fewer comorbidities, diagnosis later in the study period, higher socioeconomic status, and treatment with multimodal therapy (Supplemental eTable 3). Included patients contributed a median of 7 ESAS assessments (IQR 4-12), for a total of 14,953 unique ESAS assessments included in the analysis. Median survival was 20 months (IQR 11-39). Overall Proportion of Patients Reporting Severe Symptoms The proportion of patients reporting at least one severe score for each symptom during the study period is presented in Table 2 . The most frequently reported severe symptoms at any time during the first 12 months after diagnosis were lack of appetite (n=918, 52%), tiredness (n=787, 45%) and poor wellbeing (n=713, 40.7%). Over 20% of patients reported severe depression and over 25% reported severe anxiety over the observation period. Proportion of Patients Reporting Severe Symptoms by Month Figure 2 plots the proportion of patients reporting severe symptoms by month in the 12 months following diagnosis. The highest symptom burden is within the first five months following diagnosis, with moderate improvement in symptom burden in the second half of the first year. At month 12, approximately 15% of patients reported severe lack of appetite, 15%
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Patient Symptoms in Esophageal Cancer
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reported severe tiredness, and 12% reported severe poor wellbeing. In the subgroup undergoing neoadjuvant
chemoradiotherapy
and
surgery,
the
median
start
and
end
time
of
chemoradiotherapy is marked in Figure 3. Characteristics Associated with Severe Symptoms Characteristics associated with severe scores for all symptoms included female sex, high comorbidity, lower socioeconomic status (greatest deprivation), urban residence, and symptom assessment temporally close to diagnosis. Table 3 shows factors associated with severe lack of appetite, tiredness, and poor wellbeing (the most prevalent severe symptoms). Supplemental eTable 4 and Supplemental eTable 5 show factors associated with other severe physical and psychological symptoms, respectively. Of note, lack of appetite was the only symptom that had an association with diagnosis year; the risk of reporting severe lack of appetite decreased over the years of the study. Other symptoms did not improve or worsen over the eight-year study period. Increasing age was associated with increased risk of reporting severe lack of appetite and nausea. Treatment modality was not associated with report of severe symptoms, except that patients receiving chemoradiotherapy alone anytime during the study period were more likely to report severe pain and poor wellbeing; this effect was likely driven by the high proportion of patients reporting severe scores during and immediately following the treatment phase.
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Patient Symptoms in Esophageal Cancer
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Comment We performed a population-based study of 14,953 prospective, patient-reported symptom score assessments reported by 1,751 esophageal cancer patients over one year following diagnosis. Its generalizability is strengthened by the fact that symptom assessments were completed in the real world across sixteen cancer centers & multiple affiliates, and most eligible patients (87%) completed symptom assessments. We uncovered four important findings. First, patients undergoing curative intent therapy experience high symptom burden, which is worst in the first five months after diagnosis. Second, a considerable proportion of patients continue to experience severe symptoms even one year following diagnosis. Third, lack of appetite is the most prevalent severe symptom. Fourth, characteristics associated with severe scores vary by symptom, but characteristics common to all symptoms include female sex, high comorbidity, lower socioeconomic status, urban residence, and the first five months following diagnosis. Comprehensive assessments of patient-reported symptoms for esophageal cancer are lacking.(12, 13) Previous investigations of patient-reported outcomes have focused on questions such as the association of patient symptoms with cancer stage,(14) QoL outcomes following therapy at discrete time points,(15, 16) and especially on the prognostic value of QoL scores.(1720) A few, small studies have looked at changes in patient symptoms or QoL during therapy and over time.(16, 21, 22) Our study is an important addition to the literature as it is the first detailed analysis of patient-reported symptoms throughout the first year following diagnosis, using multicenter, prospectively-collected data in a large population of esophageal cancer patients. Our group previously examined symptom burden in the year following diagnosis for 120,745 patients with oropharyngeal, gastrointestinal, respiratory, breast, gynecologic, genitourinary, nervous system and orbit, and hematopoietic/lymphatic cancers surviving one
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Patient Symptoms in Esophageal Cancer
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year.(2) There were similarities in the characteristics associated with report of severe symptoms in the esophageal cancer population compared to the general cancer population: female sex, high comorbidity, lower socioeconomic status, urban residence, and symptom assessment in the immediate post-diagnosis period. While for all cancers, younger age was associated with increased symptom burden, in the esophageal cancer population, we found older age increased the risk of reporting severe lack of appetite and nausea. Supportive care interventions can focus on subgroups at risk of experiencing greater symptom burden. Lack of appetite appears to be a particularly challenging symptom for the esophageal cancer patient population; it was the most frequently-reported severe symptom, with 52% of patients having a score ≥7 at least once in the study period. We recognize that there are limited treatments for lack of appetite, but addressing issues that contribute to it may help. Esophageal cancer symptoms such as dysphagia, regurgitation, coughing, chest pain, or heartburn may cause patients to lose their appetite. Further, chemotherapy, radiotherapy, surgery, pain, tiredness, or depression can all individually exacerbate appetite loss. Lack of appetite should be carefully tracked and treated proactively, including assessment and management of its causes; clinical dieticians can provide support through nutritional strategies.(23) The burden of mental health symptoms we found in this study is significant, with 20% and 25% of patients reporting scores ≥7 for depression and anxiety, respectively. An ESAS screening score greater than two in depression is clinically meaningful and these patients should be referred for additional assessment and support.(24, 25) Clearly, a depression score ≥7 is truly concerning. Our results highlight the value of screening for mental health symptoms in esophageal cancer patients. Next steps in this research program include investigating what, if any, action is taken when a high depression score is reported.
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These findings are an important call-to-action for policymakers and providers to prioritize addressing patient symptoms during esophageal cancer treatment. There is evidence from a large randomized trial at Memorial Sloan Kettering Cancer Center that measuring symptoms and intervening decreases costs, benefits patient QoL, and improves survival.(26, 27) Symptom screening can inform hospitals and health systems in designing supportive care because it provides background data and understanding of what symptoms patients experience and which populations are vulnerable to high symptom burden. Symptom screening may also uncover treatment-related toxicities, psychosocial barriers and functional limitations, which can delay or limit adherence to therapy. Three methodological characteristics or limitations affect the reporting of severe symptoms in our study. First, only patients attending outpatient cancer center visits complete a symptom assessment. Patients admitted to inpatient units would be expected to have worse symptoms. Second, ESAS measurement was opportunistic, not at specified time intervals; as a result, there can be reporting bias such as only completing a symptom assessment when a patient is well enough to attend the cancer center. Third, patients had varying follow-up time if they died within one year following diagnosis, and it may be patients with the most severe scores who died. Therefore, the study may under-estimate the prevalence of severe symptoms, reinforcing the finding that symptom burden is high. Another implication of patients dying during the study period is that symptoms may not truly be improving over the course of 12 months. In conclusion, this comprehensive population-based analysis of prospective patientreported symptom scores demonstrates a high symptom burden for esophageal patients undergoing curative intent therapy. These results outline the need for better targeted treatment of common severe symptoms, and increased support for more vulnerable patients at risk for severe
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Patient Symptoms in Esophageal Cancer
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symptoms, to improve patient-centered supportive care. This information can inform and support early and ongoing symptom assessment and management warranted to improve patient-centered care and potentially quality of life in esophageal cancer patients.
Acknowledgment: This study is supported by the Sherif and MaryLou Hanna Chair in Surgical Oncology Research at Sunnybrook Health Sciences Centre. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and LongTerm Care (MOHLTC). Parts of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI) and by Cancer Care Ontario (CCO). The analyses, opinions, results and conclusions reported in this paper are those of the authors and are independent from ICES, MOHLTC, CIHI, and CCO. No endorsement by any of these organizations is intended or should be inferred.
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References 1. Darling GE. Quality of life in patients with esophageal cancer. Thorac Surg Clin 2013;23(4):569-575. 2. Bubis LD, Davis L, Mahar A et al. Symptom burden in the first year after cancer diagnosis: An analysis of patient-reported outcomes. J Clin Oncol 2018:JCO2017760876. 3. Nekolaichuk C, Watanabe S, Beaumont C. The edmonton symptom assessment system: A 15-year retrospective review of validation studies (1991--2006). Palliat Med 2008;22(2):111122. 4. Richardson LA, Jones GW. A review of the reliability and validity of the edmonton symptom assessment system. Curr Oncol 2009;16(1):55. 5. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The edmonton symptom assessment system (esas): A simple method for the assessment of palliative care patients. J Palliat Care 1991;7(2):6-9. 6. Watanabe SM, Nekolaichuk C, Beaumont C, Johnson L, Myers J, Strasser F. A multicenter study comparing two numerical versions of the edmonton symptom assessment system in palliative care patients. J Pain Symptom Manage 2011;41(2):456-468. 7. Tran K, Zomer S, Chadder J et al. Measuring patient-reported outcomes to improve cancer care in canada: An analysis of provincial survey data. Curr Oncol 2018;25(2):176-179. 8. Hui D, Shamieh O, Paiva CE et al. Minimal clinically important differences in the edmonton symptom assessment scale in cancer patients: A prospective, multicenter study. Cancer 2015;121(17):3027-3035. 9. Selby D, Cascella A, Gardiner K et al. A single set of numerical cutpoints to define moderate and severe symptoms for the edmonton symptom assessment system. J Pain Symptom Manage 2010;39(2):241-249. 10. Selby D, Chakraborty A, Myers J, Saskin R, Mazzotta P, Gill A. High scores on the edmonton symptom assessment scale identify patients with self-defined high symptom burden. J Palliat Med 2011;14(12):1309-1316. 11. Yelland LN, Salter AB, Ryan P. Performance of the modified poisson regression approach for estimating relative risks from clustered prospective data. Am J Epidemiol 2011;174(8):984-992. 12. Jacobs M, Macefield RC, Blazeby JM et al. Systematic review reveals limitations of studies evaluating health-related quality of life after potentially curative treatment for esophageal cancer. Qual Life Res 2013;22(7):1787-1803. 13. Parameswaran R, McNair A, Avery KN et al. The role of health-related quality of life outcomes in clinical decision making in surgery for esophageal cancer: A systematic review. Ann Surg Oncol 2008;15(9):2372-2379. 14. Kidane B, Ali A, Sulman J, Wong R, Knox JJ, Darling GE. Health-related quality of life measure distinguishes between low and high clinical t stages in esophageal cancer. Ann Transl Med 2018;6(13):270. 15. Noordman BJ, Verdam MGE, Lagarde SM et al. Effect of neoadjuvant chemoradiotherapy on health-related quality of life in esophageal or junctional cancer: Results from the randomized cross trial. J Clin Oncol 2017:JCO2017737718. 16. Safieddine N, Xu W, Quadri SM et al. Health-related quality of life in esophageal cancer: Effect of neoadjuvant chemoradiotherapy followed by surgical intervention. J Thorac Cardiovasc Surg 2009;137(1):36-42.
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17. Kidane B, Sulman J, Xu W et al. Baseline measure of health-related quality of life (functional assessment of cancer therapy-esophagus) is associated with overall survival in patients with esophageal cancer. J Thorac Cardiovasc Surg 2016;151(6):1571-1580. 18. Djarv T, Lagergren P. Six-month postoperative quality of life predicts long-term survival after oesophageal cancer surgery. Eur J Cancer 2011;47(4):530-535. 19. Djarv T, Metcalfe C, Avery KN, Lagergren P, Blazeby JM. Prognostic value of changes in health-related quality of life scores during curative treatment for esophagogastric cancer. J Clin Oncol 2010;28(10):1666-1670. 20. Quinten C, Martinelli F, Coens C et al. A global analysis of multitrial data investigating quality of life and symptoms as prognostic factors for survival in different tumor sites. Cancer 2014;120(2):302-311. 21. Blazeby JM, Farndon JR, Donovan J, Alderson D. A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma. Cancer 2000;88(8):17811787. 22. Trudel JG, Sulman J, Atenafu EG, Kidane B, Darling GE. Longitudinal evaluation of trial outcome index scores in patients with esophageal cancer. Ann Thorac Surg 2016;102(1):269275. 23. Arends J, Bachmann P, Baracos V et al. Espen guidelines on nutrition in cancer patients. Clin Nutr 2017;36(1):11-48. 24. Bagha SM, Macedo A, Jacks LM et al. The utility of the edmonton symptom assessment system in screening for anxiety and depression. Eur J Cancer Care (Engl) 2013;22(1):60-69. 25. Ripamonti CI, Bandieri E, Pessi MA, Maruelli A, Buonaccorso L, Miccinesi G. The edmonton symptom assessment system (esas) as a screening tool for depression and anxiety in non-advanced patients with solid or haematological malignancies on cure or follow-up. Support Care Cancer 2014;22(3):783-793. 26. Basch E, Deal AM, Kris MG et al. Symptom monitoring with patient-reported outcomes during routine cancer treatment: A randomized controlled trial. J Clin Oncol 2016;34(6):557565. 27. Basch E, Deal AM, Dueck AC et al. Overall survival results of a trial assessing patientreported outcomes for symptom monitoring during routine cancer treatment. JAMA 2017;318(2):197-198.
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Table 1: Characteristics of patients receiving symptom screening; n=1751, 87% (row percent). No Symptom Screening Symptom Screening (excluded, n=260) (included, n=1,751)
Variable
p-value
2009
72 (30.6%)
163 (69.4%)
2010
49 (22.1%)
173 (77.9%)
2011
29 (12.3%)
207 (87.7%)
2012
16 (6.4%)
233 (93.6%)
2013
28 (10.3%)
245 (89.7%)
2014
33 (11.8%)
246 (88.2%)
2015
19 (6.6%)
267 (93.4%)
2016
14 (6.1%)
217 (93.9%)
65.67 ± 10.83
63.38 ± 10.58
0.001
Female
64 (15.1%)
360 (84.9%)
0.14
Male
196 (12.4%)
1,391 (87.6%)
Low
193 (12.1%)
1403 (87.9%)
High
67 (16.1%)
348 (83.9%)
Major urban
247 (13.5%)
1,584 (86.5%)
Rural
11 (7.1%)
143 (92.9%)
(lowest)1
36 (9.3%)
352 (90.7%)
2
33 (8.1%)
372 (91.9%)
3
61 (15.2%)
341 (84.8%)
4
66 (16.8%)
328 (83.2%)
(highest) 5
62 (15.1%)
348 (84.9%)
Residency Status
Non-immigrant
239 (12.8%)
1,634 (87.2%)
Immigrant
21 (15.2%)
117 (84.8%)
Treatment
CRT
43 (6.4%)
632 (93.6%)
117 (31.9%)
250 (68.1%)
CRT & Surgery
59 (8.2%)
661 (91.8%)
Chemotherapy & Surgery
41 (16.5%)
208 (83.5%)
Diagnosis year
Age (mean ± SD) Sex
Comorbidity
Rurality
Deprivation Quintile
Surgery only
<0.001
0.01
<0.001
<0.001
0.61
<0.001
CRT = chemoradiotherapy.
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Patient Symptoms in Esophageal Cancer
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Table 2: Number of patients reporting any severe symptom at least once during the study period. Symptom
Number of patients (%)
Lack of Appetite
918 (52.4%)
Tiredness
787 (45.0%)
Poor Wellbeing
713 (40.7%)
Drowsiness
536 (30.6%)
Anxiety
463 (26.4%)
Pain
447 (25.5%)
Nausea
425 (24.3%)
Depression
359 (20.5%)
Shortness of breath
345 (19.7%)
16
June 2019 Table 3: Multivariable analysis for characteristics associated with severe lack of appetite, tiredness, and poor wellbeing. Covariate Sex Age
Lack of Appetite Male Female <50 50-59 60-69
70-79 ≥80 Immigration Non-immigrants status Immigrants Rural Rurality Index Urban Deprivation quintile
Diagnosis year
(highest) 5 (lowest) 1 2 3 4 2009 2010 2011 2012 2013 2014 2015 2016
Tiredness
Poor Wellbeing
RR Reference 1.19 Reference
LCL UCL pvalue
RR
LCL UCL
pvalue
RR
LCL UCL
pvalue
1.05
1.34
0.01
1.25
1.08
1.44
0.003
1.32
1.13
1.55
<.001
1.31 1.34 1.33 1.43 Reference 0.85
1.04 1.08 1.05 1.04
1.63 1.67 1.67 1.95
0.02 0.01 0.02 0.03
1.05 1.09 1.16 1.03
0.82 0.86 0.90 0.73
1.35 1.38 1.49 1.46
0.67 0.48 0.26 0.86
1.12 1.14 1.24 1.07
0.84 0.87 0.93 0.72
1.48 1.50 1.66 1.60
0.44 0.35 0.15 0.73
0.67
1.08
0.17
0.96
0.75
1.23
0.77
0.92
0.69
1.22
0.54
Reference 0.96 Reference
0.81
1.14
0.65
1.19
0.95
1.49
0.13
1.10
0.87
1.40
0.41
0.79 0.90 0.85
0.66 0.77 0.72
0.94 1.06 1.01
0.01 0.21 0.07
0.68 0.87 0.89
0.55 0.72 0.73
0.85 1.04 1.09
0.001 0.13 0.27
0.66 0.85 0.97
0.52 0.70 0.79
0.84 1.05 1.19
<.001 0.13 0.74
0.87 Reference
0.73
1.03
0.11
0.99
0.81
1.20
0.89
0.94
0.76
1.17
0.60
0.75 0.91
0.59 0.74
0.95 1.12
0.02 0.38
0.79 0.70
0.64 0.56
0.97 0.88
0.02 0.002
1.06 1.05 1.00 1.01
0.80 0.80 0.77 0.78
1.39 1.38 1.30 1.32
0.69 0.71 0.99 0.92
0.93 1.06 1.17 0.99
0.68 0.79 0.88 0.74
1.26 1.43 1.54 1.33
0.64 0.68 0.28 0.93
0.61 0.69 0.65
0.49 0.55 0.52
0.77 0.85 0.82
<.001 <.001 <.001
0.85 1.09 1.00
0.65 0.84 0.76
1.12 1.40 1.30
0.26 0.52 0.99
0.83 0.98 0.89
0.62 0.75 0.66
1.12 1.29 1.20
0.22 0.90 0.45
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Patient Symptoms in Esophageal Cancer Comorbidity
Low High Surgery only
June 2019
Reference 1.14 Reference 1.12 1.01
1.00
1.31
0.06
1.34
1.16
1.56
<.001
1.21
1.02
1.42
0.03
CRT 0.93 1.35 0.25 1.19 CRT & Surgery 0.83 1.23 0.91 0.91 Chemo & 0.87 0.68 1.11 0.27 0.94 Surgery 1 Reference Month from diagnosis 2 1.23 1.06 1.43 0.01 1.31 3 1.22 1.04 1.42 0.01 1.64 4 1.12 0.94 1.32 0.20 1.46 5 1.09 0.91 1.30 0.34 1.37 6 0.93 0.76 1.13 0.46 1.18 7 1.00 0.83 1.21 0.97 1.24 8 0.95 0.77 1.16 0.60 1.26 9 0.81 0.65 1.01 0.06 1.05 10 1.10 0.75 0.58 0.97 0.03 11 0.91 0.64 0.49 0.84 0.001 12 1.21 0.81 0.64 1.04 0.10 RR = relative risk. LCL = lower confidence limit. UCL = upper confidence limit.
0.95 0.72
1.48 1.14
0.13 0.40
1.35 1.04
1.05 0.80
1.75 1.35
0.02 0.77
0.71
1.24
0.67
1.04
0.76
1.42
0.81
1.10 1.37 1.20 1.12 0.95 0.99 1.00 0.82 0.85 0.68 0.95
1.57 1.97 1.77 1.67 1.47 1.54 1.58 1.35 1.41 1.22 1.55
0.003 <.001 <.001 0.002 0.14 0.06 0.05 0.71 0.46 0.54 0.12
1.17 1.25 1.13 1.10 0.93 1.06 0.99 0.78 1.10 0.92 0.97
0.95 1.01 0.91 0.87 0.71 0.82 0.76 0.57 0.83 0.69 0.73
1.45 1.54 1.42 1.40 1.21 1.36 1.29 1.06 1.45 1.24 1.30
0.14 0.04 0.27 0.42 0.58 0.65 0.94 0.11 0.52 0.60 0.85
Treatment modality
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June 2019 Figure Legends
Figure 1: Cohort diagram. RCC = regional cancer center. Figure 2: Proportion of patients reporting severe symptom scores by month of assessment in the first year following diagnosis. Trendlines do not to represent continuous data. Figure 3: Proportion of patients treated with preoperative chemoradiotherapy and surgery reporting severe symptom scores by month of assessment in the first year following diagnosis. Trendlines do not to represent continuous data.
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June 2019 Supplemental Material
eTable 1: Data sources for the study eTable 2: Definitions for receipt of treatment eTable 3: Characteristics of patients by number of symptom screening assessments completed; n=1751 (row percent). eTable 4: Multivariable analysis for characteristics associated with severe nausea, pain, and shortness of breath eTable 5: Multivariable analysis for characteristics associated with severe anxiety, depression, and drowsiness eFigure 1: Cancer Care Ontario ESAS form Supplemental Methods: Variable definitions.
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