Consistency between patients and families in recognizing cancer chemotherapy side effects: A questionnaire survey

Abstract Background Although the side effects of cancer chemotherapy impair a patient's quality of life, family members' awareness of side effects may relieve patient anxiety and distress. Aim We investigated whether patients and their families were consistent in recognizing the occurrence and severity of symptomatic side effects of chemotherapy treatment for cancer. Methods and results This was a prospective observational study. We administered a questionnaire survey to patients and family members to assess the frequency of occurrence (1: never, 2: almost never, 3: sometimes, 4: frequently, 5: almost always, 6: unknown) and the degree of severity (1: mild, 2: moderate, 3: severe, 4: extremely severe, 5: unknown) of physical and psychological symptoms associated with cancer chemotherapy. Weighted Kappa and Cramer coefficients were used to assess consistency between the two groups. We surveyed 20 pairs of patients (5 men, 15 women) and their families (10 men, 10 women); 17 pairs lived together. The median age was 65.5 years (interquartile [IQR], 58.75, 69.25) for patients and 61.00 years (IQR, 47.25, 71.25) for family members. Of patients, 17 had solid cancer, and three had leukemia. Family members mostly recognized objectively visible symptoms such as hair loss and development of spots and keratinization. However, it was difficult for families to detect invisible subjective symptoms such as weakness, dysesthesia, depressed mood, and unarticulated anxiety. Conclusions The results indicated that recognition of invisible subjective symptoms in patients undergoing chemotherapy was difficult even for family members. Therefore, a multidisciplinary approach in which various medical professionals actively communicate with both patients and families is important. Information sharing in collaboration with patients and families could increase understanding of the patient's condition and optimize patient care.


| INTRODUCTION
The number of tumor-bearing patients has increased worldwide in recent years. Globally, 18.1 million people had cancer and 9.6 million people died from the disease in 2018, 1 and cancer deaths are predicted to double by 2040. 1 A cancer statistics forecast for Japan reported a predicted number of cancer cases and deaths for 2019 of approximately 1 million and 380 000, respectively. Cancer is no longer a rare disease-indeed; it affects one in two Japanese people. 2 Medical progress has resulted in the development of many treatments for cancer, and various types of treatment are now available. [3][4][5][6][7] Consequently, the overall survival of patients with cancer has improved annually. However, cancer treatment, especially chemotherapy, causes various side effects, such as fatigue, nausea, vomiting, and hair loss. [8][9][10] The willingness of patients to undergo cancer treatment declines according to the severity of chemotherapy side effects. 11,12 Although many therapeutic drugs have been used to mitigate the side effects of chemotherapy (and some drugs can reduce or eliminate side-effect symptoms), chemotherapy inevitably causes symptoms such as pain. Therefore, to minimize distress, it is important for patients who undergo chemotherapy to receive support from individuals who can recognize side effects, understand the patient's suffering, and sympathize with their physical and psychological pain. Such individuals usually comprise medical personnel (pharmacists, nurses, or doctors) or the patient's family.
Pharmacists approach patients with cancer from the perspective of pharmaceutical care. Active intervention by pharmacists in the treatment process enables patients with cancer to better control side effects such as vomiting, and thus improves their quality of life (QOL) and treatment satisfaction. 13,14 Similarly, Bando, Onishi, and Imai reported that nursing support improves co-occurring symptoms associated with cancer therapy and can give patients hope. 15 Additionally, Kamijo and Miyamura found that spirituality had a considerable effect on patient QOL, demonstrating the importance of psychological evaluation and care for patients. 16 Therefore, the support of interdisciplinary teams can improve patient QOL by approaching patient care from different perspectives.
Medical doctors tend to underestimate side effects experienced by patients. 17,18 Therefore, physicians may not fully understand the extent of side effects in patients receiving chemotherapy, leading to patient frustration and greater suffering. Because physicians play a central role in interdisciplinary teams, it is possible that their underestimation of side effects in patients receiving chemotherapy affects the choice of medical care, with serious effects on the physical and psychological condition of patients. Moreover, patients may become wary of chemotherapy, which makes it harder for them to continue cancer treatment.
To break this negative cycle arising from the underestimation of chemotherapy side effects, it is essential to accurately recognize side effects as soon as possible and to adequately convey patient information to medical personnel, including doctors. As family members are closest to the patient, they may play an important role in this process.
Family support gives patients with cancer a sense of security and improves their QOL. 19 Because families of patients with cancer understand and sympathize with patient experiences of side effects or difficulties associated with chemotherapy, family members can be instrumental in providing appropriate support to patients. However, to do this, families must be able to adequately recognize the occurrence and severity of side-effect symptoms in patients receiving chemotherapy. However, it is unclear to what extent family members accurately recognize these symptoms. Therefore, in this study, we investigated the degree of concordance between patients and their families in recognizing the occurrence and severity of various chemotherapy side-effect symptoms.
The findings may inform collaborations between medical personnel and families to support patients with cancer.

| Question items
The questionnaire items were based on the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). 20 This is a measurement system developed by the National Cancer Institute to assess symptomatic adverse events experienced by patients in cancer clinical trials. As candidate questionnaire items, we selected those items from the PRO-CTCAE that were consensually recognized by medical doctors, two nurses, and one pharmacist as associated with cancer treatment. To determine the appropriateness of the selected items, we conducted a preliminary Chemotherapy-associated symptoms comprised 19 items: fever, vertigo, weakness, stomatitis, dysgeusia, nausea, vomiting, constipation, diarrhea, anorexia, skin eruptions, spots and keratinization, edema, nail degeneration, dysesthesia, hair loss, depressed mood, and unarticulated anxiety. Ratings of the frequency of symptom occurrence were divided into six categories, and we constructed dummy variables corresponding to these categories (1: never, 2: almost never, 3: sometimes, 4: frequently, 5: almost always, 6: unknown). Ratings of the degree of severity were divided into five categories (1: mild, 2: moderate, 3: severe, 4: extremely severe, 5: unknown). We also asked about side-effect symptoms that the patients found particularly troubling using an open-ended question. Additionally, we collected information about type of cancer, cancer staging, and age at cancer diagnosis for each patient, and the relationship between the patient and their family. Data on sex and age for the two groups were collected at the time of the survey.

| Statistical analysis
Descriptive statistics were used to evaluate the characteristics of each variable. To analyze differences in recognition of the occurrence and severity of each chemotherapy-associated symptom in each patientfamily pair, we used weighted Kappa coefficients. Cramer's coefficient was used to confirm the association between chemotherapy-related symptoms in patient and family groups. The statistical analyses were conducted using R software, version 3.6.2 (The R Foundation for Statistical Computing, Vienna, Austria). Values of p < .05 were considered significant.

| Participant characteristics
We received questionnaire responses from 23 patients and their families (i.e., 23 patient-family pairs). Of the 23 pairs, three were excluded because the patients had not been treated with cancer chemotherapy.
The characteristics of the remaining 20 pairs are shown in Table 1 Table S1). A total of 10 patients were still undergoing cancer chemotherapy treatment (Table 1). More than half of patients responded "frequently" or "almost always" with respect to the occurrence of weakness, dysgeusia, constipation, nail degeneration, dysesthesia, hair loss, depressed mood, and unarticulated anxiety, and reported that these symptoms were severe (Table 2).
Responses to the open-ended question about the side-effect symptoms that patients found particularly troubling showed the same pattern (data not shown).
Family members mostly responded "unknown" to questions about the occurrence and severity of the patients' symptoms (Table 2).

| Agreement between patients and family
To evaluate the one-to-one correspondence between patient and family responses, we used weighted Kappa coefficients (Table 3).

| Association between question items
To evaluate the consistency between each question item, we calculated Cramer coefficients. Table 4 shows the relationship between items for which the coefficients were above 0.80. In the patient group, there was a high correlation between the occurrence and Occurrence of symptoms (never/almost never/sometimes/frequently/ almost always/unknown), n symptoms in patients with cancer. 28 If medical professionals shared family reported patient information, they could provide optimal support for the patient's symptoms. Hence, the presence of family and their information about the patient can serve as a bridge to and among medical professionals such as doctors, nurses, and pharmacists.
Invisible subjective symptoms such as weakness, dysesthesia, depressed mood, and unarticulated anxiety are frequently occurring side effects. 9,11,30 Our results showed that it was difficult for family members to recognize these symptoms in patients. The severity of dysesthesia was strongly associated with psychological side effects in the patient group but not in the family group. Physical side effects may affect the patient's experience of psychological side effects. 31,32 Therefore

ACKNOWLEDGMENTS
The authors are grateful to the patients and families who participated in this study. We also thank Ms Kouzai and Ms Ehara of Kumamoto University Hospital for their help developing the questionnaire items and collecting the data. The authors wish to thank the personnel of the Cancer Salon Network Kumamoto in Japan. We thank Analisa Avila, ELS, and Diane Williams, PhD, of Edanz Group (https://enauthor-services.edanz.com/ac) for editing a draft of this manuscript.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

AUTHORS' CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.