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A Review of the Literature on Multiple Co-occurring Symptoms in Patients With Colorectal Cancer Who Received Chemotherapy Alone or Chemotherapy With Targeted Therapies

Tantoy, Ilufredo Y. MS, RN; Cataldo, Janine K. PhD, RN; Aouizerat, Bradley E. PhD, MAS; Dhruva, Anand MD; Miaskowski, Christine PhD, RN

doi: 10.1097/NCC.0000000000000343
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Background: Patients with colorectal cancer (CRC) rarely experience a single symptom associated with their disease and its treatment.

Objective: Purpose of this literature review was to summarize the current state of knowledge of multiple co-occurring symptoms in CRC patients who received chemotherapy (CTX) alone or CTX with targeted therapies.

Methods: Comprehensive literature search was conducted from 1990 to 2014. These studies were evaluated in terms of the occurrence of multiple co-occurring symptoms in CRC patients who received CTX alone or CTX with targeted therapies; the most common symptom assessment and quality of life (QOL) instruments used; and the associations identified between select demographic and treatment characteristics, QOL, and multiple co-occurring symptoms.

Results: Only 5 studies met this review’s inclusion criteria. Two studies compared symptoms in patients who received CTX alone or CTX with targeted therapies, and only 1 study reported on symptom occurrence. Of the 5 studies identified, only 2 used the same instrument to assess symptoms, and only 2 studies evaluated for associations between demographic and treatment characteristics and symptom burden, as well as QOL outcomes.

Conclusions: Given the larger number of patients with CRC, as well as the increased number of CRC patients who will receive targeted therapies with or without CTX, future studies need to describe the occurrence, severity, and distress of multiple co-occurring symptoms and their impact on CRC patients’ QOL.

Implications for Practice: To deliver effective symptom management interventions, the most common, severe, and distressing symptoms that CRC patients experience need to be identified.

Author Affiliations: Department of Physiological Nursing, School of Nursing (Mr Tantoy and Drs Cataldo, Aouizerat, and Miaskowski), School of Medicine (Dr Dhruva), and Institute for Human Genetics (Dr Aouizerat), University of California, San Francisco.

This study was funded by a grant from the National Cancer Institute (NCI, CA134900). C.M. is an American Cancer Society Clinical Research professor and is funded by a K07 award from the NCI (CA168960). I.Y.T. is funded by a National Institute of Health T32 grant (T32NR007088).

The authors have no conflicts of interest to disclose.

Correspondence: Ilufredo Y. Tantoy, MS, RN, Department of Physiological Nursing, University of California, San Francisco, 2 Koret Way, N631Y, San Francisco, CA 94143 (Ilufredo.tantoy@ucsf.edu).

Accepted for publication December 1, 2015.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the third leading cause of cancer deaths in the United States.1 Despite an increased awareness of CRC screening, the American Cancer Society estimates that 132700 new cases of CRC will be diagnosed in 2015.1 Today, patients with CRC are treated with surgery, radiation therapy, chemotherapy (CTX), and/or targeted therapies depending on the stage of their disease at the time of diagnosis.2 Because targeted therapies were developed to block the key regulators of a cancer’s growth and development, they have become an effective treatment strategy for patients with CRC. Of note, several reviews suggest that the use of targeted therapies has improved the toxicity profile of treatments for CRC as compared with CTX alone.3–5 In addition, some evidence suggests that patients tolerate targeted therapies better than traditional CTX and that survival rates increase in patients on targeted therapies.6

Patients with CRC rarely experience a single symptom associated with their disease and its treatment. Over the past decade, our group7–9 and others10–12 have evaluated multiple co-occurring symptoms in patients with cancer, which is more reflective of their experience. However, the majority of this research has focused on a description of the number and severity of symptoms in patients with a variety of cancer diagnosis.7,9,13–15 Additional research is warranted within a specific diagnosis such as CRC to determine the co-occurrence and severity of multiple symptoms that are common as well as unique to these oncology patients.

While several studies in patients with a variety of cancer diagnoses suggest that symptoms can occur in clusters,16 no studies were identified that evaluated for symptom clusters in a homogenous sample of patients with CRC. Therefore, this review focused on studies of multiple co-occurring symptoms in patients with CRC as an initial effort to describe these patients’ symptom experiences. When multiple co-occurring symptoms are not addressed, they can impair patients’ ability to carry out activities of daily living, reduce their functional status, and decrease their quality of life (QOL).17 In addition, multiple co-occurring symptoms can complicate treatment outcomes and decrease overall survival.13 Therefore, the identification of common multiple co-occurring symptoms in CRC patients and their impact on patients’ QOL is an integral component of effective symptom management.18

While advances in treatments for CRC, such as targeted therapies, continue to become available, clinical experience and a limited amount of research19 suggest that multiple co-occurring symptoms continue to be a challenge for CRC patients. However, no comprehensive review has summarized the findings from studies that evaluated multiple co-occurring symptoms in CRC patients who received CTX alone or CTX with targeted therapies. Therefore, the purposes of this review are to (1) describe the most common symptom assessment and QOL instruments that were used in these studies; (2) describe the occurrence and severity of multiple co-occurring symptoms in CRC patients who received CTX alone or CTX with targeted therapies; (3) summarize the associations identified between select demographic and treatment characteristics and multiple co-occurring symptoms; and (4) summarize the associations between multiple co-occurring symptoms and QOL outcomes. We hypothesized that compared with patients who received only CTX patients who received CTX and targeted therapy would have fewer and less severe, multiple co-occurring symptoms.

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Methods

For this review, a systematic electronic literature search was conducted using PubMed, EMBASE (Excerpta Medica Database), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases. Key words used when searching the databases were colorectal cancer AND drug therapy AND symptom AND quality of life. An additional inclusion criterion was that the article was published in English between 1990 and 2014 (targeted therapies were not approved until the 1990s.). Studies were included if they met all of the following criteria: (1) evaluated the prevalence of multiple co-occurring symptoms; (2) included CRC patients who received CTX alone or CTX with targeted therapies; and (3) used a valid and reliable instrument (eg, M. D. Anderson Symptom Inventory [MDASI],20 Memorial Symptom Assessment Scale [MSAS]21) to evaluate multiple co-occurring symptoms. Studies were excluded if symptom clusters were identified for evaluation and if current active treatment regimens included only surgery, radiation therapy, or chemoradiotherapy.

The search strategy yielded 246 studies identified in PubMed, 204 studies in EMBASE, and 28 studies in CINAHL. A total of 473 studies were removed from the analysis because the majority of these studies did not evaluate multiple co-occurring symptoms in CRC patients. In addition, duplicate articles across the databases were eliminated. Based on the prespecified search criteria, a total of 5 studies were identified.20–24

Two tables were generated to summarize the 3 studies of multiple co-occurring symptoms in patients with CRC who received CTX alone20,22,24 (Table 1) and the 2 studies of patients with CRC who received CTX with targeted therapies21,23 (Table 2). Both tables are organized using the following evaluation criteria: author, year, purpose, study design (ie, cross-sectional, longitudinal), sample characteristics (ie, sample size, age, gender, diagnosis, setting, time since diagnosis, previous treatments, current treatments, use of targeted therapy), symptom assessments (ie, instruments, number of symptoms assessed, dimensions of symptoms assessed), major findings, strengths, and limitations. Because only 5 studies were identified, the results and discussion sections of this article summarize the findings across these 5 studies.

Table 1

Table 1

Table 2

Table 2

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Results

Description of the Studies

Four of the 5 studies that evaluated for multiple co-occurring symptoms in patients with CRC used a descriptive, cross-sectional design.20–22,24 The fifth study used a descriptive, longitudinal, repeated-measures design.23 Across these 5 studies, retrospective data were used in 4.20–22,24 The sample sizes ranged from 104 patients21 to 5442 patients,22 and 3 of the 5 studies had less than 250 patients.21,23,24 Across the 5 studies, the weighted grand mean age was 59.5 years, and gender distribution was approximately equal. In 3 of the 5 studies,21,23,24 100% of the patients had CRC, and in 1 study,20 49.6% of the patients had colon cancer, and 50.4% had rectal cancer. In a fifth study,22 55.5% of the patients had CRC, and 44.5% had lung cancer.

All 5 studies were conducted in outpatient settings. Only 1 of the 5 studies reported the patients’ previous treatment regimens.20 All 5 studies reported that patients received CTX as one of their current treatment modalities. Only 2 studies reported symptom data on patients with and without targeted therapies.21,23 In terms of geographic locations, 2 studies were conducted in the United States,22,23 1 in Turkey,24 1 in Sweden,21 and 1 in China.20

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Symptom Assessment and QOL Instruments

Symptom assessment instruments. A number of instruments were used to evaluate multiple co-occurring symptoms. All 5 studies used a multidimensional symptom assessment instrument (ie, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-QLQ],22,24 Patient Care Monitor [PCM],23 MSAS,21 MDASI20). Two of the studies used the EORTC-QLQ,22,24 1 used the PCM,23 1 used the MDASI,20 and 1 used the MSAS.21 In addition, 2 studies22,24 utilized single symptom assessment instruments to evaluate additional symptoms (eg, anxiety [ie, State Trait Anxiety Inventory],24 depression [ie, Beck Depression Index,24 Center for Epidemiological Studies–Depression Scale22]).

Number and dimensions of symptoms assessed. The number of symptoms assessed ranged from a minimum of 7 symptoms22 to a maximum of 32.21 The 1 symptom dimension that was assessed across all 5 studies was severity. In 1 study,21 occurrence, frequency, severity, and distress were assessed, whereas in another study,20 interference from symptoms was assessed.

Functional status and QOL instruments. Generic and disease specific instruments were used to evaluate QOL in 3 of the 5 studies. In these studies, 1 study20 used a functional status instrument (ie, MDASI), and another study24 used a cancer-specific QOL instrument (ie, EORTC-QLQ). Only 1 study22 utilized both a generic (ie, Medical Outcomes Study Short-Form 36) and a disease specific (ie, EORTC-QLQ) instrument to evaluate the effects of multiple co-occurring symptoms on patients’ QOL.

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Occurrence and Severity of Multiple Co-occurring Symptoms

Occurrence of multiple co-occurring symptoms. The occurrence of symptoms was evaluated in only 1 study.21 In this study, using the MSAS, the mean number of symptoms was 10.3 (range, 0–32; SD, 7.7). Using the MSAS classifications, the most common physical symptoms experienced by more than 40% of the patients were numbness/tingling in the hands/feet (64%), lack of energy (62%), feeling drowsy (49%), nausea (45%), shortness of breath (43%), and dry mouth (42%). The most common psychological symptoms were difficulty sleeping (46%) and worrying (44%).

Severity of multiple co-occurring symptoms. While the severity of multiple co-occurring was reported in all 5 studies, the findings were inconsistent. In 1 study,22 51% of patients reported at least 1 symptom of moderate/severe intensity, whereas in another study,23 it was noted that patients experienced moderate to severe symptoms (defined by a PCM item score of ≥4, at some point during second-line therapy), and 67% of patients reported fatigue as the most common symptom occurring at moderate to severe levels. In 1 study that evaluated 32 symptoms using the MSAS,21 for almost all of the symptoms, patients reported higher scores for frequency than for severity or distress. Of the 5 studies, only 1 study reported the range of severity scores for 7 symptoms.23 Compared with patients who received CTX with targeted therapies, patients who received CTX alone had a higher rate of moderate to severe nausea. In addition, compared with patients who received cetuximab, patients who received bevacizumab had significantly (P < .0001) lower (ie, better) rash scores than did patients in the CTX-only group.23

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Associations Between Patient Characteristics and Multiple Co-occurring Symptoms

Associations between demographic characteristics and the severity of multiple co-occurring symptoms were evaluated in 2 studies.20,22 In 1 study,20 patients with more severe symptoms were 60 years or older, more likely to be female, had a lower body mass index, were single or divorced, were living in a suburban area, and had stage III colon cancer. In the second study,22 moderate or severe symptoms were significantly more likely to be associated with younger age, Hispanic or Latino ethnicity; being female, unmarried, and less educated; having a lower income; being uninsured; having more comorbidities; being diagnosed with late-stage cancer; and having received treatment more recently.

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Association Between Multiple Co-occurring Symptoms and QOL Outcomes

The associations between multiple co-occurring symptoms and functional status or QOL outcomes were evaluated in 3 of the 5 studies.20,22,24 In 1 study,24 global QOL scores were significantly lower in patients with higher anxiety scores (State Trait Anxiety Inventory ≥45) and higher depressive symptom (Beck Depression Index ≥17) scores. In the second study,20 the authors reported that results from their study were consistent with other studies that demonstrated that higher self efficacy scores were associated with lower symptom severity and less symptom interference with daily life. Although 1 study utilized the EORTC-QLQ to evaluate multiple co-occurring symptoms,22 the investigators did not describe the relationships among these symptoms and QOL outcomes.

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Discussion

This review is the first to summarize the findings from studies that examined multiple co-occurring symptoms in CRC patients who received CTX alone or CTX with targeted therapies. Across the 5 studies included in this review, only 2 studies21,23 compared symptoms in patients who received CTX with or without targeted therapies. In addition, only 1 longitudinal study was identified.23 Given the larger number of patients with CRC, as well as the significant toxicities associated with CTX for CRC, it is surprising that only 5 studies have systematically evaluated symptom burden in these patients.

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Symptom Assessment and QOL Instruments

Of the 5 studies identified for this review, only 2 used the same assessment instrument to assess symptoms in CRC patients (ie, EORTC-QLQ).22,24 This finding is not surprising, given the number of valid and reliable instruments that are available to assess multiple co-occurring symptoms in oncology patients.25,26 In addition, a question remains about the most appropriate symptoms to assess in CRC patients.27 Findings from this review suggest that little is known about the frequency, severity, and distress of symptoms in CRC patients and how these symptom dimensions change over time. Of note, across the 5 studies in this review, the most common instrument was the EORTC-QLQ, which contains a symptom severity scale with only 7 symptoms. However, the 2 studies that used the EORTC-QLQ22,24 did not report data on the severity of each symptom.

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Occurrence and Severity of Multiple Co-occurring Symptoms

In the 1 study that reported on symptom occurrence, CRC patients reported an average of 10.3 of 32 symptoms using the MSAS. This finding is consistent with 2 systematic reviews,28,29 as well as findings from our research team7,8 and others30,31 that regardless of diagnosis oncology patients receiving active treatment experience a large number of unrelieved symptoms. In terms of the occurrence rates for specific symptoms, only 1 study reported the occurrence rates for unrelieved symptoms.21 The 5 most common symptoms were numbness/tingling in the hands/feet (64%), lack of energy (62%), feeling drowsy (49%), difficulty sleeping (46%), and nausea (45%).

A surprising finding is the lower occurrence rates for fatigue, which in most studies of patients receiving CTX32–35 occurs in more than 80% of patients. For example, in 1 study,32 fatigue was reported as the chief complaint by 51.1% of the patients with occurrence rates that ranged from 34% to 64%. In addition, the relatively high rate of numbness/tingling is consistent with 2 studies,36,37 in which a subset of patients with CRC who received a CTX regimen that contained oxaliplatin reported this symptom. Additional research is warranted to assess the occurrence rates for common symptoms in CRC patients across their disease trajectory. In addition, given the advances in CRC treatments, studies are needed that evaluate for differences in the occurrence rates for common symptoms in patients who do and do not receive targeted therapies.

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Associations Between Demographic and Treatment Characteristics and Multiple Co-occurring Symptoms

Several demographic and treatment characteristics were associated with increases in symptom burden. For example, in 2 studies20,22 and consistent with previous studies of symptoms in oncology patients receiving CTX,35,37 being female was associated with more severe symptoms. However, given that only 2 studies evaluated for associations between demographic and treatment characteristics and symptom burden in CRC patients, a more detailed evaluation is warranted to identify high-risk patients.

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Associations Between Multiple Co-occurring Symptoms and QOL Outcomes

Only 2 studies20,22 described associations between symptoms and QOL outcomes. While the data reported suggest that higher scores on anxiety and depression instruments were associated with lower global QOL scores22 and that positive correlations were found between patients’ ability to self-manage their symptoms and their functional status,20 no studies evaluated associations between multiple co-occurring symptoms and QOL in patients with CRC.

One of the primary purposes of this review was to compare symptom burden in CRC patients who received CTX alone or CTX with targeted therapies. While current estimates suggest that approximately 25% of CRC patients who have metastases at the time of diagnosis receive targeted therapies,38,39 only 1 study addressed this question. In this study, an instrument that evaluated only 8 specific symptoms (ie, rash, dry skin, itching, nail changes, nausea, vomiting, diarrhea, burning sensation in hands or feet) was used. The only difference identified was that compared with patients who received CTX with a targeted therapy, patients who received only CTX reported a higher rate of moderate to severe nausea. Additional research is warranted to determine if a differential symptom burden occurs in CRC patients who do or do not receive targeted therapies with their CTX. Moreover, future studies of multiple co-occurring symptoms need to use comprehensive symptom assessment instruments (ie, National Institutes of Health–supported advances in measurement science through PROMIS [the Patient Reported Outcomes Measurement Information System network])40,41 that evaluate multiple dimensions of the patient’s symptom experience.

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Summary and Conclusions

Given that approximately 5% of Americans will be diagnosed with CRC in their lifetime,1 and more patients with CRC will receive targeted therapies with and without CTX,42 additional studies of multiple co-occurring symptoms are warranted. Future studies need to describe the occurrence, as well the severity, frequency, and distress of multiple co-occurring symptoms and their impact on QOL in CRC patients. In addition, changes in these symptom dimensions across the patients’ disease trajectory are warranted to be able to develop more targeted and effective symptom management interventions for these patients.

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Keywords:

Chemotherapy; Colorectal cancer; Quality of life; Symptoms; Targeted therapy

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