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Symptom Experiences in Colorectal Cancer Survivors After Cancer Treatments

A Systematic Review and Meta-analysis

Han, Claire J. PhD, MSN, RN; Yang, Gee S. PhD, MSN, RN; Syrjala, Karen PhD

Author Information
doi: 10.1097/NCC.0000000000000785

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer among both men and women in the United States.1 In 2017, 135 430 individuals were newly diagnosed with CRC and 50 260 were projected to die from the disease.1 Despite this, increasing numbers of patients are surviving CRC. In the United States, the survival rate is 90% at 5 years for patients with localized cancer and 63% at 5 years for patients across all stages of CRC combined. Although early diagnosis and advanced treatment have increased CRC survival rates, many individuals live with long-term side effects that span the cancer treatment trajectory.2 Colorectal cancer survivors have special healthcare challenges and needs.3 Once the side effects from primary cancer treatments subside, many CRC survivors continue to report a high burden of symptoms such as fatigue, bowel dysfunction, depression, and insomnia.3 This symptom burden is the major factor associated with quality of life (QOL) after treatment ends and with overall CRC survivorship.3

Nonspecific symptoms in CRC survivors include changed bowel habits, general abdominal discomfort, weight loss, and fatigue.4 By contrast, symptoms in advanced CRC cases—including blood and mucus in stool, nausea, vomiting, and some emergency conditions, such as bowel obstruction or perforation—have been directly linked to the cancer itself or treatment side effects or both.4 The multimodality of CRC treatments (eg, extensive abdomino-pelvic surgery, pelvic radiation therapy, chemotherapy, and surgical resection) can further alter bowel function, sphincter loss, and permanent ostomies. This often leads to sexual dysfunction, psychological distress, physical and social limitations, and insomnia.5 These multiple symptoms often persist after treatment ends and continue into survivorship.5 To ensure maximum long-term well-being, proper monitoring and management of these physical and psychological symptoms are needed for CRC survivors.6

Adverse symptoms after cancer treatments may also impact CRC survivors’ ability to adhere to the American Cancer Society (ACS) recommendations for physical activity and nutrition, key lifestyle factors linked to survival outcomes.7 In a recent prospective cohort study of patients with stage III colon cancer who finished treatments (N = 999), those who followed the ACS guidelines had a 42% lower risk of death. However, many CRC survivors face ongoing health challenges, such as gastrointestinal (GI) distress, psychological problems, and fatigue.7 These adverse symptoms in turn have been negatively associated with adherence to a lifestyle consistent with the ACS guidelines on physical activity and nutrition.7

Given that the number of CRC survivors is dramatically increasing, more attention is needed to understand posttreatment symptom experiences to develop tailored interventions to increase holistic well-being among long-term CRC survivors. To date, a few studies have focused on symptomology in this patient group after cancer treatments, compared with research on survivors of other major diseases such as breast, lung, and prostate cancer.3,6 We found only 1 integrative review that examined a small set of studies (N = 5) focused on symptoms in CRC survivors receiving chemotherapies.3 Only 2 of these studies evaluated associations between demographic and treatment characteristics, symptom burden, and QOL outcomes. Tantoy and colleagues3 state that symptoms in posttreatment CRC survivors are poorly understood, specifically as they relate to risk factors and impacts on life. This lack of information also makes it difficult to develop effective symptom management guidelines.3

To address this research gap and improve the QOL among CRC survivors, we performed a systematic review of literature on symptom experiences in CRC survivors after cancer treatments. Our primary aim was to systematically review (1) the symptoms that adult CRC survivors experience, (2) the risk factors for these symptoms, and (3) the impacts of these symptoms. Our secondary aim was to conduct meta-analyses to evaluate the frequency and the severity of symptoms in adult CRC survivors after cancer treatments.

Conceptual Framework

The conceptual framework (Figure 1) for this study is based on the Symptom Management Model.8 As seen in Figure 1, this model addresses the intercorrelations among 3 major concepts (ie, symptom experiences, symptom management strategies, and symptom outcomes). The 3 domains—person, environment, and health and illness—are contextual variables influencing symptom management.8 For symptom experience concept, an individual’s experience consists of perception, evaluation, and response to a symptom, processes that are bidirectionally related. Effective symptom management is based on each person’s unique assessment of his/her symptom experience. Symptom outcomes—including functional status, self-care, emotional status, costs, mortality, QOL, and morbidity—result from both symptom experience and management.8 In our review, we analyzed and synthesized study data by mapping symptom experiences of CRC survivors to elements of the Symptom Management Model (Figure 1). We focused on “symptom experiences,” “symptom outcomes,” and “risk factors of symptoms (under the concept of symptom management strategies)” in the Symptom Management Model.

Figure 1
Figure 1:
Theoretical framework: symptom management model for CRC survivors. Note. Symptom experiences, disease outcomes, and symptom management strategies are interrelated within the contexts of health and illness, person, and environment. Symptoms of CRC, potential impacts of CRC symptoms, and potential risk factors of CRC symptoms are focused on understanding the dynamics and interplay of these various health components to inform effective interventions for CRC survivors. CRC indicates colorectal cancer; QOL, quality of life. Adapted from Dodd et al.8

Methods

Search Strategies and Data Sources

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline for systematic review and meta-analysis,9 we conducted a systematic literature review to integrate findings from quantitative studies. Our systematic literature research examined 7 electronic databases: Scopus, CINAHL, Medline via PubMed, Web of Science, EMBASE, Cochrane Library (Review and CENTRAL), and PsycINFO. We focused on symptom experiences among CRC survivors after cancer treatments. Using MeSH terms and manual searches, the key words examined were “colorectal cancer,” “colon cancer,” “rectal cancer,” “cancer survivor*,” “after treatment*,” “chemotherapy,” “radiotherapy,” “surgery,” “symptom*,” “bowel,” “GI,” “psychological distress,” “fatigue,” “pain,” “peripheral,” “sleep,” “stress,” “cognitive,” “neuropathy,” “urinary,” and “sexual,” in combination with “risk factors,” “outcomes,” and “impact.” Other eligible studies were identified by reviewing the cited references from the obtained published studies.

Inclusion and Exclusion Criteria

Studies were included if they met the following criteria: (a) published over the last 15 years from June 2004 to May 2019; (b) reported symptoms after any cancer treatments in CRC survivors using quantitative measures; (c) based on original or experimental data; (d) examined patients 18 years or older with CRC; and (e) published in English. Studies were excluded studies if they (a) presented only qualitative results; (b) were not published in English; (c) were review papers or editorials, meta-syntheses, theory-based works, dissertations, and case studies; (d) collected symptom data only before and/or during cancer treatments; (e) reported only incidence of symptom diagnosis (eg, generalized anxiety disorders, major depressive disorders); or (f) were focused on caregivers.

Because sexual dysfunction and urinary symptoms in CRC survivors have already been systematically reviewed,10,11 we excluded studies that primarily assessed these symptoms from our analyses. There were no restrictions regarding when symptoms were assessed after cancer treatments. This could have occurred after treatments, including the recovery phase, or during the long-term survivorship phase. This approach ensured all relevant literature was included.

Study Selections and Screening

Two authors (C.J.H. and G.S.Y.) independently assessed the collected articles for study eligibility. All titles, abstracts, and full-text articles were reviewed independently by each author based on the inclusion and exclusion criteria. Discrepancies were resolved by discussion. In the case of disagreement between the 2 authors, a third author (K.S.) was available for arbitration.

Methodological Quality Appraisal

Two authors (C.J.H. and G.S.Y.) independently evaluated the methodological quality of each article using the Critical Appraisal Skills Programme (CASP) checklists (2017) for quantitative observational studies. The CASP checklists, consisting of 12 questions, appraise research rigor and risk of investigator bias.12 Each question is answered with “yes,” “can’t tell,” or “no.” There is, however, no established standard of the CASP checklists to designate an article as high or low quality.12 Using an arbitrary threshold, commonly used for critical appraisal of a research study,12 we evaluated an article as “high” quality if it met at least 80% of the checklist criteria (eg, 10/12 questions in each study), “low” quality if it met 50% or less of the criteria, and “medium” quality if it met more than 50% and less than 80% of the criteria. In cases of continued disagreement between the 2 authors, a third author (K.S.) arbitrated.

Data Extraction and Data Synthesis

In this review, the following variables were extracted: study aims; publication year; study design; country of research; setting of research; sample size; participant characteristics; methods of measuring symptoms; symptom experiences; risk factors for adverse symptoms; outcomes of symptoms; and other symptom-related factors, results, and conclusions. Data were extracted into self-developed standardized forms by the first author (C.J.H.) and verified for accuracy and completeness by the other authors (G.S.Y. and K.S.). Discrepancies were resolved through consensus-building discussions among the 3 authors. We synthesized the extracted data and presented the findings as narrative descriptions and descriptive statistics.

Meta-analytical and Statistical Methods

To get more precise estimates of symptom frequency and severity reported among CRC survivors, a meta-analysis was used to combine the symptom data from multiple studies to increase power over findings from individual studies.13,14 The pooled frequency and severity of symptoms were computed with weighted mean and standard errors, along with 95% confidence interval (CI).13,14 We included only studies that reported the frequency (percentage of research participants with a symptom) and/or the mean severity of a symptom using numerical rating scales. In addition, the pooled frequency and severity estimates were analyzed only if symptom frequency or severity was present in at least 2 studies per symptom. For severity data, mean severity was converted to a 0 to 100 scale from different scales, where a higher score indicates worse symptoms.13,14 Because there are no validated cutoff points to interpret a pooled mean severity as mild, moderate, or severe, we compared individual symptoms based on their relative value of pooled mean severity.

Forest plots were presented with pooled mean estimates of frequency or severity of symptoms with 95% CIs. Heterogeneity was analyzed with Q statistics as a measure of squared variance in which P < .10 was considered statistically significant, and with I2 statistics (I2 < 25.0%, no heterogeneity; I2 > 75.0%, high or extreme heterogeneity). For data with high heterogeneity, random-effects model results were presented. Otherwise, we chose fixed-effects model results. A 2-sided P < .05 was considered statistically significant.

For descriptive statistical analysis, the Statistical Package for the Social Sciences version 23.0 (SPSS, Inc, Chicago, Illinois) was used. For meta-analysis, the statistical analyses, including forest plots, were performed using Comprehensive Meta-Analysis (version 2.2.050; Biostat, Engelwood, New Jersey).

Results

Included Studies and Methodological Quality Evaluation

The search strategies yielded 473 published articles after excluding duplicates. A review of titles and abstracts reduced the number of relevant studies to 57 and a total of 35 were identified for final analysis, following assessment of the full-text articles. Three of these studies were excluded from the meta-analyses owing to the absence of symptom severity and frequency data15 or symptoms were reported on only 1 study.16,17 A flowchart of our literature search is depicted in Figure 2, and details for the 35 studies are described in Tables 1 and 2. Results from evaluating each of the 35 quantitative studies using CASP tools are reported in Supplementary Tables 1 and 2, http://links.lww.com/CN/A29. The interrater agreement between the 2 authors was 98.3%. No studies were excluded due to low quality.

Figure 2
Figure 2:
Article search flow diagram for systematic review and meta-analyses.
Table 1
Table 1:
Studies Focusing on Multiple Symptoms in Colorectal Cancer Survivors (N = 6)
Table 2
Table 2:
Studies Focusing on Single Symptom in Colorectal Cancer Survivors (N = 29)

Study Characteristics

Two-thirds of the studies (n = 21) had cross-sectional designs, whereas 14 studies had longitudinal, prospective designs (Tables 1 and 2). The longitudinal studies measured symptoms at baseline and after cancer treatments. In these longitudinal studies,15,17–19,25,28,31,32,37,40,41,44,46,47 overall, symptoms worsened over time (the longest follow-up: 2 years after chemotherapy).17 Studies included in our review were conducted in various countries of the 35 studies, including the United Kingdom (n = 9), United States (n = 9), Australia (n = 8), and Asia (n = 4, including 1 in Taiwan and 3 in China). Most participants (n = 24/35 studies) were men, whereas 2 studies included only female participants.32,45 The age range of research participants across all the studies was 50 to 70 years, with an average age of 63 years.

The timeframe for assessment ranged from 24 hours after treatment39 to 11 years after cancer diagnosis.26 The most common time point to assess symptoms was between 6 months and 2 years after treatment.15–19,21,36,40,44,47 Patient symptomology was also assessed an average of 3 to 6 years after initial cancer diagnosis.2,5,23,24,27,29–32,37,38,42,43,45 In 6 studies, the time point for symptom assessment was not specified.22,33–36,45 In symptom dimensions (ie, frequency, severity, and distress), frequency and/or severity were used in 34 studies, except for 1 study.15 In 14 studies,25–31,33,35,36,40,42,43,45 both severity and frequency were reported while either severity or frequency was reported in other 21 studies. A variety of validated tools were used to measure CRC symptoms in the 35 studies. The most frequently used tool was the European Organization into Research and Treatment of Cancer (EORTC) instruments (eg, EORTC-C30, -C38, -C29, or Chemotherapy Induced Peripheral Neuropathy [CIPN20]) in 8 studies.2,5,19,21,23,26,27,45 The Hospital Anxiety and Depression Scale was the second most common assessment tool, used in 6 studies (Tables 1 and 2).18,31,33–36

Symptom Experiences

MULTIPLE SYMPTOMS

Six of the 35 studies2,5,18–21 assessed overall symptomology, including physical and psychological symptoms (Table 1). Gastrointestinal symptoms, psychological distress, fatigue, or insomnia were evaluated. Gastrointestinal symptoms and fatigue were the major adverse symptoms reported among study participants. Several GI symptoms—including abdominal pain, diarrhea, constipation, fecal incontinence, blood and mucus in stool, and nausea and/or vomiting—frequently occurred following cancer treatments such as surgery or chemotherapy.2,5,18–21 After chemotherapy, other reported symptoms included pelvic floor pain,5 stomach aches, pain in the rectum, perianal skin irritation, and soreness were reported after rectal surgery.18

Although we excluded studies primarily focused on sexual and urinary symptoms given our exclusion criteria, 2 studies assessing multiple patient symptoms5,21 reported findings on urinary and sexual dysfunction. Colorectal cancer survivors experienced moderate urinary problems and mild sexual dysfunction after surgery.5,21 These symptoms were also seen in 1215 long-term CRC survivors more than 5 years after diagnosis, with a 30% frequency of urinary problems and a 20% occurrence of sexual dysfunction.5

SINGLE SYMPTOM

Twenty-nine of the 35 studies focused primarily on single symptoms experienced in CRC survivors (Table 2). These included peripheral neuropathy (n = 9, Table 2a), psychological distress such as anxiety and depression (n = 7, Table 2b), fatigue (n = 6, Table 2c), body image distress (n = 4, Table 2d), cognitive impairment (n = 2, Table 2e), and insomnia (n = 1, Table 2f).

Meta-Analyses of Symptoms After Cancer Treatments

HETEROGENEITY AMONG STUDIES

Overall heterogeneities in each symptom subgroup were high, with I2 greater than 75% in both pooled frequency and severity analyses; thus, overall, random-effects model results were used (Table 3). However, we chose fixed-model results to determine frequency of body image distress and for assessing the severity of fecal incontinence, embarrassment with bowl movement, abdominal pain, appetite loss, nausea and/or vomiting, and sore mouth and tongue.

Table 3
Table 3:
Meta-analyses of Symptom Frequency and Severity (Pooled Estimates and Heterogeneity of Included Articles per Symptom)

POOLED MEAN FREQUENCY OF SYMPTOMS

As seen in Figure 3, a total of 22 studies were included in the pooled analysis of system frequency.2,5,20,23–33,35–37,39,40,42,43,45 Ten post–cancer treatment symptoms were analyzed: body image distress, peripheral neuropathy, fecal incontinence, bloating, fatigue, constipation, diarrhea, abdominal pain, anxiety and depression (Table 3, Figure 3). Among these symptoms, the pooled mean frequency was highest for body image distress (78.5%; 95% CI, 75.6–81.0), followed by peripheral neuropathy (61.8%; 95% CI, 37.1–81.6). Approximately one-third of posttreatment patients reported GI symptoms of constipation, diarrhea, or abdominal pain, whereas about half experienced fecal incontinence or bloating.

Figure 3-A
Figure 3-A:
Forest plot of pooled frequencies of symptoms in colorectal cancer survivors after cancer treatments via meta-analyses. Note: Random effect model was used except for body image distress. CI indicates confidence intervals; FRQ, frequency; LCL, low confidence interval limit; UCL, upper confidence interval limit; WGHT, weight of each study.
Figure 3-B
Figure 3-B:
Forest plot of pooled frequencies of symptoms in colorectal cancer survivors after cancer treatments via meta-analyses. Note: Random effect model was used except for body image distress. CI indicates confidence intervals; FRQ, frequency; LCL, low confidence interval limit; UCL, upper confidence interval limit; WGHT, weight of each study.
Figure 3-C
Figure 3-C:
Forest plot of pooled frequencies of symptoms in colorectal cancer survivors after cancer treatments via meta-analyses. Note: Random effect model was used except for body image distress. CI indicates confidence intervals; FRQ, frequency; LCL, low confidence interval limit; UCL, upper confidence interval limit; WGHT, weight of each study.

POOLED MEAN SEVERITY OF SYMPTOMS

As seen in Figure, a total of 22 studies were included in the pooled analysis of symptom severity.18,19,21,22,25,27–31,33–36,40–47 Fifteen symptoms were included: fatigue, insomnia, body image distress, anxiety, depression, fecal incontinence, embarrassment with bowel movements, abdominal pain, diarrhea, appetite loss, peripheral neuropathy, nausea and/or vomiting, sore mouth and tongue, blood and mucus in stool, and constipation. After cancer treatments, fatigue was the most severe symptom (pooled mean severity, 50.1; 95% CI, 45.1–55.2), followed by insomnia (mean, 39.9; 95% CI, 14.6–65.3) and body image distress (mean, 36.4; 95% CI, 28.8–44.1), on a scale of 0 to 100 (Table 3 and Figure 4).

Figure 4-A
Figure 4-A:
Forest plot of pooled severities of symptoms in colorectal cancer survivors after cancer treatments via meta-analyses. Note: Fixed effect model was used for fecal incontinence, embarrassment with bowel movement, abdominal pain, appetite loss, nausea and/or vomiting, and sore mouth and tongue. Pooled mean severity data on a 0–100 scale. CI indicates confidence intervals; FRQ, frequency; LCL, Low confidence interval limit; UCL, upper confidence interval limit; WGHT, weight of each study.
Figure 4-B
Figure 4-B:
Forest plot of pooled severities of symptoms in colorectal cancer survivors after cancer treatments via meta-analyses. Note: Fixed effect model was used for fecal incontinence, embarrassment with bowel movement, abdominal pain, appetite loss, nausea and/or vomiting, and sore mouth and tongue. Pooled mean severity data on a 0–100 scale. CI indicates confidence intervals; FRQ, frequency; LCL, Low confidence interval limit; UCL, upper confidence interval limit; WGHT, weight of each study.
Figure 4-C
Figure 4-C:
Forest plot of pooled severities of symptoms in colorectal cancer survivors after cancer treatments via meta-analyses. Note: Fixed effect model was used for fecal incontinence, embarrassment with bowel movement, abdominal pain, appetite loss, nausea and/or vomiting, and sore mouth and tongue. Pooled mean severity data on a 0–100 scale. CI indicates confidence intervals; FRQ, frequency; LCL, Low confidence interval limit; UCL, upper confidence interval limit; WGHT, weight of each study.
Figure 4-D
Figure 4-D:
Forest plot of pooled severities of symptoms in colorectal cancer survivors after cancer treatments via meta-analyses. Note: Fixed effect model was used for fecal incontinence, embarrassment with bowel movement, abdominal pain, appetite loss, nausea and/or vomiting, and sore mouth and tongue. Pooled mean severity data on a 0–100 scale. CI indicates confidence intervals; FRQ, frequency; LCL, Low confidence interval limit; UCL, upper confidence interval limit; WGHT, weight of each study.

Potential Risk Factors of Symptoms

Risk factors related to symptom development were extracted from the original studies (Tables 1 and 2). Being female was significantly associated with the severity of various symptoms, including GI symptoms,2 psychological distress,31,33,34 body image distress,44,45 and fatigue.40 Certain cancer treatments were positively associated with severe symptoms.2,15,19,20,23–30,42 For example, receiving oxaliplatin-based chemotherapy was significantly associated with severity of peripheral neuropathy in CRC survivors.23–30 Younger patient age and younger age at diagnosis were strong predictors of long-term symptom severity in CRC survivors.2,5,19,20,45 Individuals diagnosed at a younger age experienced higher levels of emotional distress and body image distress, whereas those diagnosed at an older age experienced frequent sexual and urinary dysfunction.5 Low education,31,36,37 low self-efficacy,34 and unmarried or single patients19,31,34,36 were more likely to experience severe symptoms, including psychological distress. Patients with late stages of CRC (stage III or IV),20,33,34 multiple comorbidities including psychological disorders,16,22,27,38,42,43 and poor physical and social functioning16,22,31,34,36,43 also reported more severe symptoms.

The experiences of having ostomies were associated with various GI symptoms (eg, fecal incontinence, unintentional fecal release), psychological distress (eg, embarrassment with bowel movements, anxiety concerning a stoma), fatigue, and sexual distress.5,19,21,46 Poor nutritional levels, low blood cell counts and serum calcium levels were positively associated with fatigue.39 Symptoms were often interrelated. For example, psychological distress, poor sleep quality, and fatigue were associated,38–43,48 whereas GI symptoms and psychological distress were associated with body image distress.45

Potential Impact of Symptoms

Various potential impacts of CRC symptoms were identified in 35 studies. Overall, poor physical, emotional, and social QOL, interferences with daily life, caregiver burdens, and financial burdens emerged (Tables 1 and 2). Poor QOL was the most frequently reported impact of adverse symptomology.2,17,19,21–23,26,27,40,44,46 Gastrointestinal symptoms were associated with lower physical activity in long-term cancer survivors.2,18 Adverse symptoms also negatively impacted sexual functioning and relationships.5,21,33,45 For example, GI symptoms (eg, fecal incontinences, abdominal bloating), embarrassment with bowel movements, having a stoma, and sexual dysfunction were associated with poor sexual relationships with partners. Acute or chronic adverse symptoms also took an emotional toll, increasing depression, fatigue, and anxiety.40,44,46 The symptom burden also limited social functioning and interactions with family, friends, and community.2,31,36 Patient caregivers also suffered in a variety of ways. Cancer-related symptoms were associated with caregivers’ emotional distress, low physical functioning, poor general health, and low overall QOL.19,21 These individuals often experienced increased depression, fatigue, insomnia, anxiety, and physical tiredness related to their caregiving burdens. Finally, adverse CRC symptoms increased ongoing financial difficulties and concerns for caregivers and in CRC survivors alike.18,33

Discussion

This is the first systematic review and meta-analyses we are aware of that comprehensively addresses symptom experiences in CRC survivors after cancer treatments. Our review extends the existing literature by synthesizing the findings of individual studies into a detailed overview of symptomology, including risk factors and impacts of symptoms in this vulnerable population. Most of the included 35 studies focused on a single symptom rather than assessing multiple symptoms. Findings indicate many CRC survivors experienced persistent adverse symptoms after cancer treatments. Our meta-analyses showed that body image distress and peripheral neuropathy were the most prevalent, whereas fatigue and insomnia were the most severe. We also found that GI symptoms and psychological distress were also major symptoms. Patient factors associated with worse symptoms include younger age, female sex, cancer stage III or IV at diagnosis, lack of family and social support, oxaliplatin-based chemotherapy, and having a stoma. Such symptoms negatively affect physical and emotional status, social functioning and relationships, QOL, caregivers’ physical and emotional health, and financial status. Our research documents the importance of long-term clinical management persistent negative symptoms after cancer treatment ends.

Given that a multidimensional approach is needed for effective symptom management, the Symptom Management Model8 offers guidance for helping CRC survivors who experience a variety of unremitting symptoms. Our findings are supported from the Symptom Management Model, by confirming that optimal symptom management depends on understanding the dynamics and interplay of these various health components. Our findings may help researchers understand major risk factors of symptom burden and develop effective symptom management strategies for CRC survivors within this holistic conceptual model.

Our meta-analysis of symptom frequency and severity across the 32 of 35 studies revealed that body image distress was a prevalent and severe symptom in CRC survivors (pooled frequency, 78.5%, ranked first; pooled severity: mean, 36.5, ranked third) among symptoms included in our analyses. A higher degree of body image distress was associated with experiences with having past or current stomas.44,45,47 A qualitative study of CRC survivors found that having a stoma increased body image distress, which in turn led to physical and emotional problems, low self-esteem, social isolation, loss of appetite, food restriction, uncertainty, limited social functioning and interaction, impaired sexual relationships and intimacy with partners, and poor QOL.49 In this qualitative study, compared with other cancer-related symptoms, body image distress was rarely discussed between clinicians and CRC survivors.49 Thus, it is needed for healthcare providers to engage with patients on this issue continuously both before and after cancer treatments, specifically stoma surgery.

In our meta-analyses, fatigue was the most severe symptom (mean, 50.1), with a pooled frequency of 38.1% (ranked fifth) among symptoms included in our analyses. Fatigue is also frequent and is a severe symptom experienced after treatment for other cancer types, including leukemia and breast, lung, prostate, and ovarian cancers.48 Notably, low hemoglobin and poor nutritional status39 and anemia and digestive hemorrhages18 contribute to fatigue in CRC survivors. Disease-related digestive hemorrhages, hemolysis, and increased cytokines are potential causes of impaired iron metabolism that can cause anemia in CRC survivors.18 The loss of nutrients can also contribute to fatigue in CRC survivors.18 This is an important clinical consideration because fasting and hypermetabolism may occur after colorectal surgery.39 Chemotherapy-related side effects, such as anorexia, nausea, and vomiting, can also increase malnutrition and associated fatigue in CRC survivors.48 Cancer-related inflammation, neuroendocrine alterations, and autonomic nervous system dysregulation are also related to fatigue.48 This suggests that screening and treating anemia and nutritional status may reduce fatigue in CRC survivors. Further research is also needed on cancer-related nutritional deficiencies, anemia, and biological mechanisms to better understand, assess, and treat fatigue in CRC survivors.

Our meta-analyses found that mild GI symptoms were frequently reported in CRC survivors after cancer treatments (Figures 3 and 4). Various GI complications reported were abdominal pain, fecal incontinence, bloating, constipation, diarrhea, abdominal pain, nausea and/or vomiting, blood and mucus in stool, and appetite loss. Such symptoms can directly result from certain cancer treatments. In addition, a colon or rectal tumor itself can cause physiological bowel problems such as malabsorption, GI tract inflammation, and motility disorders.6 Our findings suggest that the awareness of GI symptoms may help both predict the risk of CRC and guide posttreatment clinical management for long-term CRC survivors.

In several cases, we found discordances in rank orders of several symptoms based on frequency versus severity. For example, peripheral neuropathy was the second most prevalent among 10 symptoms analyzed (frequency, 61.8%), but its severity was only mild (14.2, ranked 11th out of 15 symptoms). Similarly, the pooled frequency of anxiety and depression ranked 9th, and 10th respectively, whereas their pooled severities ranked 4th and 5th, respectively (Table 3). These findings highlight the importance of assessing various symptom dimensions (ie, severity, frequency) after cancer treatments, because that a patient is not complaining about a severe condition does not mean it is nonexistent or is not negatively impacting his/her overall well-being.

In our meta-analyses, we found that insomnia and psychological distress were also major symptoms in CRC survivors. Two studies of our review reported that psychological distress, insomnia, and fatigue often cooccur as a symptom cluster in CRC survivors, with a cluster analysis,19 and a principal component analysis.38 This finding is consistent with previous symptom cluster studies related to other types of cancer. Fatigue, depression, anxiety, and insomnia often occur together in breast, lung, prostate, and ovarian cancer.6 A recent study emphasizes the importance of the symptom cluster approach in identifying distinct symptom phenotypes in cancer patients and providing clinical treatments that targets cooccurring symptoms.50 It is important for clinicians to be knowledgeable about CRC symptom clusters postchemotherapy and apply it to clinical practice because it may enable them to identify symptoms that are overlooked or hidden and effectively anticipate other symptoms that might likely occur during the assessment.

Although our analysis excluded systematic reviews focused on sexual and/or urinary symptoms,10,11 our review revealed that mild to moderate sexual or urinary symptoms were reported after cancer treatments.21,33,44,45 A previous review of sexual dysfunction studies reported that approximately 50% of female and 5% to 88% of male CRC survivors reported sexual dysfunction after radiotherapy, chemotherapy, or surgery.11 Another systematic review examining both sexual and urinary dysfunction10 revealed between that 22% and 76% of CRC survivors across studies experienced these symptoms. Both these symptoms were associated with stomas, cancer treatment complications, tumor location in the lower rectum or anus, psychological distress, older age, poor QOL, and altered body image after cancer treatments.10,11 Two articles included in our analyses confirmed the impact of body image distress on poor sexual functioning and QOL.44,45 It is therefore important for researchers and clinicians to bear in mind the interplay of multiple symptoms when addressing urinary and/or sexual dysfunction in long-term CRC survivors.

Multiple predisposing factors—younger patient age, younger age at diagnosis, female sex, advanced cancer stage at diagnosis, and lack of family and social support—were associated with worse symptom experiences. Rasmussen et al4 reported that older CRC patients experienced less severe, frequent, and prolonged adverse symptoms in general than younger CRC patients did. Symptoms in older CRC patients were also less likely to be associated with cancer treatments compared with younger patients.4 Several possible explanations may exist for different symptom experiences by age. Rasmussen et al4 noted that younger or younger-onset survivors were more likely to undergo surgery and chemotherapy than older patients. Given this treatment tendency, it is not surprising younger patients may report more treatment-related symptoms, whereas symptoms in older CRC patients may be associated more with the aging process than cancer. In addition to age, cancer patients from different sociodemographic and clinical characteristics may appraise their symptoms differently.49

Our review revealed that negative symptom experiences in CRC survivors resulted in poor QOL, limited social engagement, and multilevel distress for caregivers. Of note, caregivers for CRC survivors often reported feeling depressed and stressed because of insufficient training in how to care for the patient, financial burdens, lack of social resources, or difficulty in balancing multiple caregiving roles.49 Importantly, despite the extensive involvement of family members in caring for CRC survivors, little research exists on these caregivers’ daily experiences, demands, challenges, and needs in this patient group.49 Healthcare professionals need to be aware of this often overwhelming family dynamic and provide caregivers with referrals to community resources to ease their burden.

The current study has several limitations. First, most studies in this review were conducted in the United Kingdom or United States. Results are not necessarily generalizable to other countries, particularly those with different oncology healthcare systems or different cultural views toward symptom experiences in cancer survivors. Second, it is unknown whether symptoms differ according to variable factors such as time after treatment until symptom onset or time from cancer diagnosis to treatment. Third, although this review highlights risk factors for common CRC symptoms and outcomes, it cannot explain the exact nature and direction of the association between risk factors, symptoms, and outcomes. This is because most of the included studies had cross-sectional designs. Fourth, there were inconsistencies in the assessment and reporting of symptoms across the 35 studies. Different studies used various symptom dimensions, scoring ranges, instruments, scoring interpretations, and periods to assess symptoms. Such inconsistencies and gaps in symptom assessment made it difficult to conduct a meta-analysis and compute a pooled mean severity and frequency for several symptoms from such disparate and incompatible data. In the case of several symptoms (eg, cognitive impairment), there were not 2 compatible studies to include in our meta-analyses.

More research are suggested to assess each individual symptom, including cognitive impairment, GI symptoms, and insomnia. The many burdens associated with long-term caregiving duties are another crucial area for future inquiry. To better understand persistent symptoms in CRC survivors, researchers must devise standardized assessment tools and methods, which will guide future tailored symptom interventions for patients with symptoms, who are at high risk. A consensus also is needed on the condition of symptom assessment (ie, measurement, time to assess symptoms, symptom dimensions). Lastly, given our primary aim of this review, we only focused on risk factors of symptoms, under the concept of symptom management strategies in the Symptom Management Model. Thus, future research is needed to further explore other aspects of symptom management strategies (eg, who delivers, what, and how to deliver) in CRC survivors. Such research can foster the design of tailored symptom management protocols for CRC survivors at high risk of symptom burden.

Clinical Implications

The CRC survivors in our review often reported multiple concurrent and persistent adverse symptoms that have impacted their physical, social, and psychological QOL. Study findings can help nurses and oncologists perform more informed patient assessments after cancer treatments and provide more thorough symptom management for long-term survivors. Many patients would likely benefit from a referral for CRC-specific counseling to address common concerns like body image distress, fatigue, GI symptoms, psychological distress, and poor QOL. Our findings inform patients and caregivers to consider an opportunity to strategize with healthcare providers to assure optimal symptom management and arrange for needed community support services.

Conclusion

Survivors of CRC experience multiple adverse symptoms, which often continue after cancer treatment ends. Our meta-analyses revealed that body image distress, fatigue, GI symptoms, and psychological distress are major problems for this population group. Multiple risk factors contribute to adverse symptomology, including younger patient age, female sex, and lack of family and social support. Unrelieved CRC symptoms are linked to psychological distress, financial burdens, decreased QOL and social functioning, and caregivers’ physical and emotional difficulties. There are analysis barriers related to inconsistent or incomplete data in existing studies that need to be overcome in future research. It is necessary to reach a methodological consensus on CRC symptom assessment so that investigators can obtain a conclusive understanding of the challenges faced by survivors following treatment. Future research is warranted to develop individualized symptom management strategies for CRC survivors at high risk of symptom burden.

ACKNOWLEDGMENT

The authors thank Mr. Ezra Ochshorn for English Language editing services.

References

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Keywords:

After treatments; Colon cancer; Impact; Meta-analysis; Quality of life; Rectal cancer; Risk factors; Survivorship; Symptoms; Systematic review

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