Multiple Gastrointestinal Symptoms Are Associated With Chemotherapy-Induced Nausea In Patients With Breast Cancer

Patients and settings

This study is part of a larger descriptive, longitudinal study that evaluated the symptom experience of oncology outpatients receiving chemotherapy and whose methods are described in detail elsewhere.^{16, 17} The theoretical framework for the parent study was the Theory of Symptom Management.¹⁸ In the parent study, patients were eligible if they: were ≥18 years of age; had a diagnosis of breast, GI, gynecological, or lung cancer; had received chemotherapy within the preceding four weeks; were scheduled to receive at least two additional cycles of chemotherapy; were not receiving concurrent radiation therapy; were able to read, write, and understand English; and provided written informed consent. Patients were recruited from two Comprehensive Cancer Centers, one Veteran’s Affairs hospital, and four community-based oncology programs. The same inclusion criteria and study procedures were used regardless of the patient’s cancer diagnosis.

Study procedures

The study was approved by the Committee on Human Research at the University of California at San Francisco and by the Institutional Review Board at each of the study sites.

A total of 2234 patients were approached and 1343 consented to participate (60.1% response rate). The major reason for refusal was being too overwhelmed with their cancer treatment. Of the 1343 patients who consented, 532 had a diagnosis of BC. These patients with BC were evaluated in this study.

A research staff member approached eligible patients in the infusion unit and discussed participation in the study. Written informed consent was obtained from all of the patients. Patients were recruited during their first or second cycle of chemotherapy. Depending on the length of their chemotherapy cycles (i.e., 14-day, 21-day, or 28-day), patients completed study questionnaires in their homes, a total of six times over two cycles of chemotherapy. Medical records were reviewed for disease and treatment information. Data from the enrollment assessment (i.e., prior to the patients’ second or third cycle of chemotherapy) were used in these analyses.

Instruments

Coding of the chemotherapy regimens

Using the Multinational Association of Supportive Care in Cancer (MASCC) guidelines,^25–27 each drug in the chemotherapy regimen was classified as having: minimal, low, moderate, or high emetogenic potential. The emetogenicity of the regimen was categorized into three groups (i.e., low/minimal, moderate, or high) based on the chemotherapy drug with highest emetogenic potential.

Coding of the antiemetic regimens

Each antiemetic was coded as either a neurokinin-1 (NK-1) receptor antagonist, a serotonin receptor antagonist, a dopamine receptor antagonist, prochlorperazine, lorazepam, or a steroid. The antiemetic regimens were coded into four groups: none (i.e., no antiemetic administered); steroid alone or serotonin receptor antagonist alone; serotonin receptor antagonist and steroid; or NK-1 receptor antagonist and two other antiemetics (e.g., a serotonin receptor antagonist, dopamine receptor antagonist, prochlorperazine, lorazepam and/or a steroid).

Statistical analyses

Data were analyzed using SPSS Version 27 (IBM Corporation, Armonk, NY). Descriptive statistics and frequency distributions were calculated for demographic and clinical characteristics. Appropriate parametric and nonparametric tests were used to evaluate for differences in demographic and clinical characteristics and the occurrence of GI symptoms between patients who did and did not report CIN. Multiple logistic regression analysis was used to evaluate for predictors of CIN group membership. Only those characteristics that were significantly different in the univariate analyses between patients who did and did not report CIN were evaluated in the logistic regression analysis. A backwards stepwise approach was used to create a parsimonious model. Only predictors with a p-value of <0.05 were retained in the final model.

CIN characteristics

Of the 532 patients with BC, 47.2% reported CIN in the week prior to their next cycle of chemotherapy. Of these 251 patients, 96.8% rated its severity, 98.4% rated its frequency, and 96.8% rated its distress. Of the patients who reported severity, frequency and distress associated with CIN: 13.2% of the patients rated the severity as “severe” and 2.9% as “very severe” (Fig. 1a); 20.2% of the patients rated its frequency as “frequently” and 10.5% as “almost constantly” (Fig 1b); 12.3% of the patients rated its distress as “quite a bit” and 8.2% as “very much” (Fig. 1c).

Differences in demographic and clinical characteristics

Compared to the no CIN group, patients with CIN were significantly younger; reported a lower annual income; and had a lower KPS score, a higher number of comorbidities, and a higher comorbidity score. Patients in the CIN group were more likely to have high blood pressure, depression, and back pain. In addition, a higher percentage of patients in the CIN group received chemotherapy on a 14-day cycle; received highly emetogenic chemotherapy; and received a NK-1 receptor antagonist and two other antiemetics (Table 1).

Differences in the occurrence of GI symptoms

Compared to the no CIN group, patients with CIN had significantly higher occurrence rates for: change in the way food tastes, dry mouth, lack of appetite, constipation, feeling bloated, diarrhea, mouth sores, weight loss, abdominal cramps, difficulty swallowing, and vomiting (Table 2).

Results of the logistic regression analysis

Characteristics that were significantly different between the two CIN groups in the univariate analyses were included in the backwards stepwise elimination model (i.e., age, KPS score, SCQ score, cycle length, emetogenicity of the chemotherapy regimen, antiemetic regimen, and all eleven GI symptoms). While income was significantly different between the two groups, 61 patients did not report their income. Therefore, this variable was not included in the regression analysis. Consequently, data from 502 patients with BC were included in the final model.

As shown in Table 3, seven characteristics (i.e., KPS score, dry mouth, cycle length, vomiting, constipation, change in the way food tastes, and lack of appetite) were retained in the final logistic regression model (X² = 166.96, p<.001). Patients who had a lower KPS score and who reported the occurrence of dry mouth, vomiting, constipation, change in the way food tastes, and lack of appetite were more likely to be in the CIN group. In addition, cycle length was a significant predictor of CIN group membership. Because cycle length had three groups, three pairwise contrasts were examined to interpret the effect of cycle length. The significance criteria for each of these contrasts was .017 (.05/3). Two contrasts were significant. Compared to patients who received chemotherapy on a 21-day or 28-day cycle, patients on a 14-day cycle had a 1.92 or a 4.17 increase in the odds, respectively of being in the CIN group.

GI symptoms associated with CIN occurrence

Across numerous studies,^{9, 29, 30} a GI symptom cluster, that includes CIN and many of the GI symptoms evaluated in this study, was identified in patients receiving chemotherapy. This symptom cluster is hypothesized to occur as a result of chemotherapy-induced inflammation along the entire GI tract.^31–33 Therefore, it is not surprising that patients in the CIN group reported higher occurrence rates for all eleven GI symptoms. However, dry mouth, vomiting, constipation, change in the way food tastes, and lack of appetite were the five co-occurring symptoms that were retained in the final regression model. The co-occurrence of these GI symptoms may be the result of a number of interacting mechanisms that are described below.^{31, 34–36}

The administration of chemotherapy can decrease salivary secretion.³⁷ This decrease in saliva and the direct effects of chemotherapy on the mucosal epithelium results in dry mouth and oral mucositis.³⁷ In addition, chemotherapy can change the profile of the microbiome of the oral cavity.³⁷ For example, in a study of patients with BC who received a combination of cyclophosphamide, epirubicin or methotrexate, and 5-flurouracil,³² 11% developed oral candidiasis. In our study, while mouth sores were reported by 30% of the patients in the CIN group, it did not remain significant in the regression analysis. However, patients with dry mouth were 2.08 times more likely to be in the CIN group. This finding suggests that clinicians need to perform routine assessments of the oral mucosa particularly for patients who are receiving stomatotoxic chemotherapy.

Changes in the way food tastes is another co-occurring symptom that may be related to the direct effects of chemotherapy on the oral mucosa and its microbiome. Consistent with previous reports,^{4, 7, 8} the occurrence of change in the way food tastes was associated with a 1.57 times increased risk of being in the CIN group. Of note, the co-occurrence of taste changes and CIN increases with repeated cycles of chemotherapy.⁷ In addition, in a study of taste changes in patients with BC,³² while CIN was not evaluated, dry mouth, oral mucositis, and an increase in acidophilic microflora co-occurred in patients with taste changes. Given these findings, the occurrence and severity of taste changes warrant investigation in future studies.

While only 20% of the patients in the CIN group reported vomiting, this symptom was associated with an 8.91 times increase in the odds of being in this group. Numerous factors may explain the higher rates of these two symptoms in our CIN group including: the natural co-occurrence of these two symptoms; a history of morning sickness;^{3, 10} increased emetogenicity of the chemotherapy regimen;¹⁰ inconsistent adherence with the antiemetic regimen;¹⁰ and/or a number of molecular mechanisms.^{31, 34, 38}

The co-occurrence of constipation was associated with a 2.05 increase in the odds of being in the CIN group. The etiology of constipation may be multifactorial in patients with BC receiving chemotherapy. One of the major side effects of antiemetic regimens that include serotonin and tachykinin receptor antagonists is constipation.³⁹ While not significant in the final regression model, patients in the CIN group were more likely to receive an antiemetic regimen that included a NK1-receptor antagonist. In addition, some of the most common chemotherapy regimens that patients with BC receive include drugs (e.g., taxotere) that induce constipation. The high co-occurrence rates for bloating and abdominal cramps in the CIN group may be related to constipation.

The co-occurrence of lack of appetite was associated with a 2.45 increase in the odds of being in the CIN group. Both the type of chemotherapy and the antiemetic regimen that the patient received may contribute to the development of this symptom. For example, in a study of patients with BC who received an anthracycline and cyclophosphamide regimen,⁴⁰ compared to patients who received a single dose of granisetron, patients who received multiple doses of this antiemetic were more likely to report lack of appetite. In another study,⁴¹ an association was found between the receipt of an anthracycline and cyclophosphamide regimen and the occurrence of CIN, lack of appetite, and stomatitis.

The co-occurrence of all of these GI symptoms may be the result of chemotherapy-induced epithelial inflammation along the entire GI tract.^{35, 42} In fact, in our recent study,³¹ perturbations in pathways associated with mucosal inflammation and disruption of the gut microbiome were associated with occurrence of CIN. Taken together, these findings suggest that clinicians need to assess for all of these co-occurring GI symptoms and initiate appropriate interventions to alleviate this extremely high symptom burden.

Demographic and clinical characteristics associated with CIN occurrence

This study is the first to evaluate a comprehensive list of demographic and clinical characteristics associated with the occurrence of CIN in patients with BC. While in the multivariate analyses, no demographic characteristics remained significant, KPS score and cycle length were the two clinical characteristics retained in the final model. Patients with lower functional status had an increased likelihood of being in the CIN group. The difference in KPS scores between the two CIN groups represents not only a statistically significant but a clinically meaningful difference (i.e., d = 0.56) in functional status. Given that CIN co-occurs with symptoms that have a negative impact on patients’ nutritional intake, it is plausible that their functional status may be compromised. These patients may warrant referrals to a dietician for nutritional counseling.

In our univariate analysis and consistent with previous studies, a higher percentage of patients who received highly emetogenicity chemotherapy^{1, 3, 6} and antiemetic regimens that contained a NK-1 antagonist¹⁰ were in the CIN group. However, only cycle length remained significant in the multivariate model. Compared to patients who received chemotherapy on 21- and 28-day cycles, those who received chemotherapy on a 14-day cycle, were at increased risk for being in the CIN group. Several plausible explanations exist for this association. While it was not possible due to the heterogeneity of the chemotherapy regimens in this study to evaluate the relative contribution of a specific regimen to membership in the CIN group, 88.6% of the patients who received their chemotherapy on a 14-day cycle (i.e., 156 of 203) received doxorubicin and cyclophosphamide which is known to be a highly emetogenic regimen.⁴¹ Equally plausible, this association can be partially explained by the more frequent exposure to chemotherapy. In addition, compared to patients on a 21-day, a higher percentage of patients on a 14-day cycle received highly emetogenic chemotherapy (13.2% vs 86.8%, p < 0.001, respectively). For patients on a 14-day cycle, behavioral interventions (e.g., systematic desensitization, progressive muscle relaxation) prior to and during chemotherapy may help decrease the occurrence of CIN.⁴³ In addition, future research is warranted to investigate interventions to alleviate chemotherapy-induced GI inflammatory processes that may help decrease CIN occurrence.

Limitations

Several limitations warrant consideration. Because the occurrence of CIN during the first cycle of chemotherapy is a risk factor for subsequent episodes,^{1, 44} future studies can use the MASCC antiemesis tool⁴⁵ or a daily diary to assess CIN occurrence prior to the initiation and over the course of chemotherapy. In addition, future studies need to evaluate patients’ level of adherence with their antiemetic regimen. In addition, future studies need evaluate the relationships between specific chemotherapy regimens and co-occurring GI symptoms and increased occurrence rates for CIN. While our study evaluated a large number of potential predictors that warrant confirmation, future studies should evaluate additional risk factors including: motion sickness,^{3, 10} morning sickness,¹⁰ and previous history of nausea,⁴⁶ because these risk factors may be particularly important in women with BC. Given that the majority of our patients were White, college educated, and had metastatic disease, our findings may not generalize to all patients with BC receiving chemotherapy.

Conclusions

Despite these limitations, our study is the first to describe significant associations between the occurrence of multiple GI symptoms, as well as clinically meaningful demographic and clinical characteristics, and CIN in patients with BC. Based on the findings from this study, particularly in relationship to the high occurrence rates for GI symptoms, clinicians need to assess patients for nausea and these associated symptoms. Of note, the relatively high occurrence of nausea suggests that patients may not be adhering with their antiemetic regimen. Nurses need to assess the efficacy of the antiemetic regimen, as well as patients’ adherence with it, and make modifications to decrease this distressing symptom. In addition, individualized treatment plans need to be developed for co-occurring symptoms, namely constipation and dry mouth.

Given the associations among dry mouth, change in the way food tastes, vomiting, constipation, and lack of appetite, as well as a lower level of physical function in the patients with CIN, a variety of interventions may help alleviate this symptom. For example, in two studies of patients receiving chemotherapy,^{47, 48} the intake of fish oil supplements alleviated dry mouth⁴⁸ and improved appetite.⁴⁷ While additional research is warranted on its efficacy in decreasing CIN, fish oil maintains intestinal wall integrity and decreases gastrointestinal inflammation⁴⁹ that may contribute to the occurrence of CIN.³⁴ In another study that evaluated for self-care strategies patients used to manage taste changes,⁵⁰ this symptom was associated with nausea, dry mouth, and decreased appetite. Patients who were bothered my nausea reported that adding more fats or sauces to foods and eating more flavored protein foods was helpful. Given that CIN was associated with lack of appetite and changes in the way food tastes, patients’ nutritional status needs to be monitored and referrals need to be made to dieticians.

Finally, clinicians can use the demographic and clinical characteristics found in this study to identify patients at increased risk for unrelieved CIN and initiate therapeutic interventions. In addition to the recommendations cited above, future research needs to investigate the underlying mechanisms associated with these risk factors, particularly the multiple co-occurring GI symptoms.