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Over 90% of patients with cancer experience 1 or more symptoms caused directly by cancer or its treatment. These symptoms negatively impact on the completion of planned treatment as well as patients’ health-related quality of life (HRQoL). It often results in serious complications and even life-threatening outcomes. Thus, it has been recommended that surveillance of symptom burden should be performed and managed during cancer treatment. However, differences in symptom profiles in various patients with cancer have not been fully elucidated for use in performing surveillance in the real world.
This study aims to evaluate the burden of symptoms in patients with various types of cancers during chemotherapy or radiation therapy using the PRO-CTCAE (Patient-Reported Outcome Version of the Common Terminology Criteria for Adverse Events) and its impact on quality of life.
We performed a cross-sectional study of patients undergoing outpatient-based chemotherapy, radiation therapy, or both at the National Cancer Center at Goyang or at the Samsung Medical Center in Seoul, Korea between December 2017 and January 2018. To evaluate cancer-specific symptom burden, we developed 10 subsets for using the PRO-CTCAE-Korean. To measure HRQoL, we used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Participants answered questions prior to their clinic appointments on tablets. Multivariable linear regression was used to analyze symptoms based on cancer type and to evaluate the association between the PRO-CTCAE items and the EORTC QLQ-C30 summary score.
The mean age (SD) of the patients was 55.0 (11.9) years, and 39.94% (540/1352) were male. Overall, symptoms in the gastrointestinal category were the most dominant in all cancers. Fatigue (1034/1352, 76.48%), decreased appetite (884/1352, 65.38%), and numbness and tingling (778/1352, 57.54%) were the most frequently reported. Patients reported more local symptoms caused by a specific cancer. In terms of nonsite-specific symptoms, patients commonly reported concentration (587/1352, 43.42%), anxiety (647/1352, 47.86%), and general pain (605/1352, 44.75%). More than 50% of patients with colorectal (69/127, 54.3%), gynecologic (63/112, 56.3%), breast (252/411, 61.3%), and lung cancers (121/234, 51.7%) experienced decreased libido, whereas 67/112 (59.8%) patients with gynecologic cancer and lymphoma/myeloma reported pain during sexual intercourse. Patients with breast, gastric, and liver cancers were more likely to have the hand-foot syndrome. Worsening PRO-CTCAE scores were associated with poor HRQoL (eg, fatigue: coefficient –8.15; 95% CI –9.32 to –6.97), difficulty in achieving and maintaining erection (coefficient –8.07; 95% CI –14.52 to –1.61), poor concentration (coefficient –7.54; 95% CI –9.06 to –6.01), and dizziness (coefficient –7.24; 95% CI –8.92 to –5.55).
The frequency and severity of symptoms differed by cancer types. Higher symptom burden was associated with poor HRQoL, which suggests the importance of appropriate surveillance of PRO symptoms during cancer treatment. Considering patients had comprehensive symptoms, it is necessary to include a holistic approach in the symptom monitoring and management strategies based on comprehensive patient-reported outcome measurements.
Over 90% of patients with cancer experience 1 or more symptoms caused directly by cancer or its treatment [
However, barriers to symptom monitoring are medical jargon and lack of trust [
So far, most guidelines developed for selecting symptom measures were designed for clinical trials, and there is a lack of guidance for practitioners and for performing surveillance in the real-world clinical setting [
We performed a cross-sectional study of patients undergoing outpatient-based chemotherapy, radiation therapy, or both at the National Cancer Center (NCC) at Goyang or at the Samsung Medical Center (SMC) in Seoul, Korea between December 2017 and January 2018. Eligible participants were (1) older than age 18; (2) diagnosed with cancer; (3) currently receiving chemotherapy or radiation therapy or both; and (4) those who can read, speak, and comprehend Korean. To include a more diverse sample of patients with cancer who have relatively little information about symptom burden, we aimed to recruit at least 50 patients with lymphoma, gastric, gynecologic, head and neck, and liver cancers. To simultaneously evaluate the measurement properties of all items of the PRO-CTCAE-Korean (n=124) within a single study, we aimed to recruit 1300 patients with cancer. Based on the site investigator’s assessment, patients with clinically significant cognitive impairment were excluded from the study. The sampling frame was monitored to ensure that a minimum of 15% of participants had an impaired performance status (PS), defined as an Eastern Cooperative Oncology Group (ECOG) PS of 2 or higher [
Participants answered questions prior to their clinic appointments on tablets without assistance but could request technical assistance from the study staff if required.
For cancer-specific symptom burden surveillance, we developed 10 subsets of the PRO-CTCAE-Korean (9 for specific cancers and 1 for general purpose). The PRO-CTCAE item library has been previously translated and validated in Korean [
To measure HRQoL, we used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), previously validated in Korean [
A composite-grade scoring algorithm was used to obtain single numerical grades for AEs based on multiple PRO-CTCAE items [
The symptom prevalence by composite grades of the PRO-CTCAE items is shown using a tree map. The size of the rectangles in the tree map indicates the proportion of patients with symptoms, with the darker colors indicating a higher prevalence of patients who reported symptoms as severe. Linear regression was used to analyze symptoms based on cancer type. Covariates adjusted were patient’s age, sex, ECOG, and treatment types. Linear regression was also performed to evaluate the association between the PRO-CTCAE items and the EORTC QLQ-C30 summary score [
All analyses were performed using STATA version 16 (StataCorp LP) and R 3.6.1 (R Foundation for Statistical Computing).
Study participants provided written informed consent. We gave the participants a US $5 gift card to thank them for their participation. The Institutional Review Board of the Samsung Medical Center (SMC 2020-04-157) and the National Cancer Center (NCC2017-0249) approved this study. All the research data were encrypted.
A total of 1352 patients (breast, n=411; colorectal, n=127; gastric, n=123; gynecologic, n=112; head and neck, n=56; liver, n=67; lung, n=234; lymphoma, n=112; prostate, n=57; and others, n=53) participated in this study. The mean age (SD) of the patients was 55.0 (11.9) years; 39.94% (540/1352) were male and 79.29% (1072/1352) received chemotherapy (
Gastrointestinal cancer (purple) was the most dominant among all cancers (
When we compared the symptoms across different types of cancer, patients reported more local symptoms caused by a specific cancer (
In terms of nonsite-specific symptoms, patients commonly reported concentration (587/1352, 43.42%), anxiety (647/1352, 47.86%), sadness (638/1352, 47.19%), and general pain (605/1352, 44.75%;
More than 50% of patients with colorectal, gynecologic, breast, and lung cancers and lymphoma/myeloma experienced sexual symptoms, such as decreased libido or pain during sexual intercourse (
We observed a significant decrease in the mean QLQ-C30 summary scores across worsening PRO-CTCAE scores (
Characteristics of study participants (N=1352).
Characteristics | Breast (n=411) | Colorectal (n=127) | Gastric (n=123) | Gynecologic (n=112) | Head and neck (n=56) | Liver (n=67) | Lung (n=234) | Lymphoma (n=112) | Prostate (n=57) | Others (n=53) | |||||||||||||
Age group, mean (SD) | 49.1 (9.4) | 56.4 (9.6) | 56 (11.4) | 52.8 (11) | 58.9 (11.3) | 59.7 (9.4) | 61 (9.4) | 52.9 (16.5) | 67.8 (10.2) | 55.9 (13.2) | <.01 | ||||||||||||
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Female | 409 (99.5) | 59 (46.5) | 40 (32.5) | 112 (100) | 18 (32.1) | 23 (34.3) | 82 (35.0) | 40 (35.7) | 8 (14.0) | 21 (39.6) |
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Male | 2 (0.5) | 68 (53.5) | 83 (67.5) | 0 (0) | 38 (67.9) | 44 (65.7) | 152 (65.0) | 72 (64.3) | 49 (86.0) | 32 (60.4) |
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Less than middle school | 36 (8.8) | 27 (21.3) | 28 (22.8) | 22 (19.6) | 17 (30.4) | 16 (23.8) | 79 (33.8) | 22 (19.6) | 19 (33.3) | 9 (17.0) |
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High school | 170 (41.4) | 51 (40.2) | 51 (41.5) | 51 (45.5) | 16 (28.6) | 27 (40.3) | 102 (43.6) | 46 (41.1) | 19 (33.3) | 19 (35.8) |
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More than college | 205 (49.9) | 49 (38.6) | 44 (35.8) | 39 (34.8) | 23 (41.1) | 24 (35.8) | 53 (22.6) | 44 (39.3) | 19 (33.3) | 25 (47.2) |
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Employed | 110 (26.8) | 40 (31.5) | 44 (35.8) | 11 (9.8) | 15 (26.8) | 15 (22.4) | 58 (24.8) | 37 (33.0) | 8 (14.0) | 15 (28.3) |
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Unemployed | 301 (73.2) | 87 (68.5) | 79 (64.2) | 101 (90.2) | 41 (73.2) | 52 (77.6) | 176 (75.2) | 75 (67.0) | 49 (86.0) | 38 (71.7) |
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<US $1990 | 75 (18.2) | 28 (22.0) | 44 (35.8) | 27 (24.1) | 14 (25.0) | 24 (35.8) | 84 (35.9) | 29 (25.9) | 27 (47.4) | 9 (17.0) |
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US $2000-US $3990 | 153 (37.2) | 62 (48.8) | 45 (36.6) | 55 (49.1) | 26 (46.4) | 26 (38.8) | 97 (41.5) | 41 (36.6) | 21 (36.8) | 26 (49.1) |
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≥US $4000 | 183 (44.5) | 37 (29.1) | 34 (27.6) | 30 (26.8) | 16 (28.6) | 17 (25.4) | 53 (22.6) | 42 (37.5) | 9 (15.8) | 18 (34.0) |
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0-1 | 347 (84.4) | 111 (87.4) | 87 (70.7) | 84 (75.0) | 47 (83.9) | 57 (85.1) | 190 (81.2) | 89 (79.5) | 50 (87.7) | 42 (79.2) |
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2-4 | 64 (15.6) | 16 (12.6) | 36 (29.3) | 28 (25.0) | 9 (16.1) | 10 (14.9) | 44 (18.8) | 23 (20.5) | 7 (12.3) | 11 (20.8) |
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Chemotherapy | 306 (74.5) | 105 (82.7) | 123 (100) | 94 (83.9) | 25 (44.6) | 60 (89.6) | 182 (77.8) | 109 (97.3) | 32 (56.1) | 36 (67.9) |
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Radiation | 81 (19.7) | 3 (2.4) | 0 (0) | 6 (5.4) | 15 (26.8) | 4 (6.0) | 13 (5.6) | 1 (0.9) | 19 (33.3) | 15 (28.3) |
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Both | 24 (5.8) | 19 (15) | 0 (0) | 12 (10.7) | 16 (28.6) | 3 (4.5) | 39 (16.7) | 2 (1.8) | 6 (10.5) | 2 (3.8) |
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aECOG: Eastern Cooperative Oncology Group.
Tree map representing symptom severity and prevalence by type of cancer. Colors indicate the symptom summary score. Sizes of squares are proportion. Thus, the darker the color and greater the size of a square, the more severe and more prevalent the symptom.
In this large real-world surveillance study of burden of symptoms among patients with various types of cancers undergoing chemoradiation therapy, frequency and severity of symptoms differed by cancer types. A higher symptom burden score was associated with poor quality of life, suggesting the importance of appropriate surveillance of PRO symptoms during cancer treatment.
Symptoms in the gastrointestinal category were most commonly reported among patients with different cancer types than those in other categories, and this finding is consistent with the results of a previous study [
In this study, we found that patients experienced more frequent and more severe symptoms caused by a specific cancer. For example, head and neck as well as lung and prostate cancers had relatively more oral, respiratory, and urinary tract symptoms, respectively, compared with other types of cancer. Our study findings are somewhat similar to the results of previous studies which reported that most patients (>80%) experienced symptoms related to their cancer site [
Using the PRO-CTCAE will help detect symptoms that were often underreported by health professionals [
The PRO-CTCAE includes 6 symptoms of cutaneous toxicity, which were frequently reported by our patients with lymphoma/myeloma, colorectal, gynecologic, gastric, breast, and lung cancers. Although cutaneous toxicities are the common side effects reported by patients with cancer receiving chemotherapy [
Regarding the impact of symptoms burden on HRQoL, most symptoms were associated with lower HRQoL. In particular, memory, mood, fatigue, erection, body odor, concentration, and dizziness were associated with clinically noticeable declines in HRQoL. As these symptoms were associated with daily life, they might have a greater impact on HRQoL due to their burden. In particular, fatigue was reported as one of the most common side effects of cancer that was associated with poor HRQoL, which is similar to the finding reported in a previous study [
There are several limitations to our study. First, the reporting of the symptom scores was voluntary. Thus, the receipt of symptom screening may itself bias the estimates of symptom burden because the routine collection of PROs is associated with improved clinical outcomes and increased patient satisfaction. In addition, patient factors, including male sex and advanced age, were associated with lower rates of PRO-CTCAE reporting, which could reflect differential rates of participation among patient subgroups. Second, as symptom assessments are only recorded at outpatient visits, we did not capture the symptoms of patients who are admitted to the hospital or hospice, or who are otherwise too unwell to visit clinics and may probably be the most symptomatic. In addition, because of the heterogeneity in our cohort, we did not assess the influence of treatment modalities, which will differ substantially among stages, on symptom burden. Finally, although we compared symptom burden based on disease site groups, we did not describe the symptoms of unique cancers, which may mask heterogeneity in the symptom profiles of distinct cancers within larger categories, such as lymphoma/myeloma, colorectal, head and neck/esophageal, prostate/bladder, and gynecologic cancers. Despite these limitations, this study provides guidance on symptoms that should be asked about to patients in the real-world clinical setting. This study also illustrated the feasibility of linking routinely collected PROs to large population-based health care databases.
In conclusion, the frequency and severity of symptoms differed according to the type of cancer, and the symptoms were associated with poor HRQoL. Recently, there has been an emphasis on the appropriate assessment of PRO symptoms during cancer treatment [
Symptom frequency by composite grades of PRO-CTCAE items. PRO-CTCAE: Patient-Reported Outcome Version of the Common Terminology Criteria for Adverse Events.
Difference (95% CI) of cancer-specific symptoms by types of cancer compared with other cancers.
Association between symptoms and health-related quality of life in different types of cancer.
adverse event
Eastern Cooperative Oncology Group
European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30
health-related quality of life
National Cancer Center
Patient-Reported Outcome Version of the Common Terminology Criteria for Adverse Events
performance status
Samsung Medical Center
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1I1A2074210), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (grant number 1520240), a grant (number 19182MFDS426) from the Ministry of Food and Drug Safety in 2019, and Future Medicine 20 × 30 Project of the Samsung Medical Center (SMX1210831).
The data sets generated or analyzed during this study are available from the corresponding author (JC) on reasonable request.
DK and JC were involved in the study design. ML, SYK, YJC, SS, and YJK were involved in data collection. DK, SK, and HK were involved in data acquisition and management. DK, SK, and HK were involved in data analysis. All authors were involved in results interpretation and manuscript writing. JC made the decision to submit this manuscript for publication.
None declared.