Gender Differences in Pain, Fatigue, and Depression in Patients With Cancer

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1 Gender Differences in Pain, Fatigue, and Depression in Patients With Cancer Christine Miaskowski A quick review of virtually any research topic documents the pervasiveness of sex and gender bias throughout all of science. A large portion of both animal and human research has been, and continues to be, done primarily with male subjects. This gender bias influences research results and often leads to inappropriate and questionable generalizations of research findings, usually from studies done with male participants to females. Needless to say, this bias exists in symptom management research on pain, fatigue, and depression in patients with cancer. This article reviews the evidence from the studies on gender differences in pain, fatigue, and depression in patients with cancer. It should be noted that research studies on gender differences in cancerrelated pain, fatigue, and depression are minimal in number, are restricted to studies of the differences in prevalence rates and severity scores, and for the most part have yielded inconsistent results. Additional investigations are warranted to determine whether the gender differences in prevalence rates and severity of these symptoms represent clinically meaningful differences. If these gender differences are substantiated, these findings will guide the design of studies to elucidate the underlying mechanisms for these differences, as well as the development and testing of gender specific interventions to treat cancer-related pain, fatigue, and depression. [J Natl Cancer Inst Monogr 2004;32:139 43] A quick review of virtually any research topic documents the pervasiveness of sex and gender bias throughout all of science. A large proportion of both animal and human research has been, and continues to be, done primarily with male participants. As noted by Sechzer and colleagues (1), this bias toward the inclusion of only males or the preponderance of males in research studies influences and often leads to inappropriate and questionable generalization of these findings, usually from males to females. These authors note that the effect of this bias on women s health has not been completely evaluated. Equally important is the fact that even with the National Institutes of Health requirement for the inclusion of women in clinical trials, Sechzer and colleagues found that in clinical research on lung cancer treatment, studies with male participants predominated in the literature. The authors cited that in a review of all of the papers published in the Journal of Clinical Oncology and in Cancer in 1994 on lung cancer treatment, 77% of the study participants were male. As a follow-up to their literature review, Sechzer and colleagues conducted an informal survey of scientists and asked them whether they would be willing to include women in clinical trials (1). The authors report in their article that they were told, Oh, I have no problem about including women in my studies and would be happy to do so, but female subjects are very difficult to find, or It will really cost an enormous amount of money to recruit women for my studies, and that would decrease the amount of research I could conduct. They also heard concerns that a woman s menstrual cycle would interfere with the problem being studied (p. 43). Of note, this same bias occurs in symptom management research on pain, fatigue, and depression in patients with cancer. The purpose of this article is to summarize the limited amount of research on gender differences in pain, fatigue, and depression in patients with cancer and to make recommendations for future research. It should be noted that no studies could be found on gender differences in pain, fatigue, and depression in children with cancer. GENDER DIFFERENCES IN CANCER-RELATED PAIN Recent information on acute pain management indicates that there may be gender differences in pain sensitivity and tolerance, as well as in analgesic effectiveness [for reviews, see (2 4)], and that certain chronic pain problems occur more commonly in women (5). Although chronic pain is experienced by approximately 50% of oncology outpatients (6 7) and by 80% to 90% of patients with metastatic cancer (8), little is known about gender differences in the prevalence or severity of chronic cancer pain. Only two published studies (9,10) and two unpublished studies (Miaskowski et al.) have provided data on gender differences associated with cancer pain. The results of these studies are summarized in Table 1. In a prospective study of cancer pain in 1308 outpatients with metastatic cancer (9), female oncology patients were found to be at greater risk for inadequate prescription of analgesics and were significantly more likely to experience inadequate pain management than male patients. Although Cleeland and colleagues (9) evaluated gender differences in analgesic prescriptions for cancer patients, they did not report on gender differences in pain intensity scores. A retrospective study by Turk and Okifuji (10) evaluated the pain intensity scores of cancer patients (n 143) who were experiencing chronic pain for gender differences. Using the McGill Pain Questionnaire and the Multidimensional Pain Inventory, no significant gender differences were found in pain intensity scores reported by these patients. In a recently completed randomized clinical trial that tested the effectiveness of a psychoeducational intervention (PRO- SELF Pain Control Program) compared with standard care in improving cancer pain management (11 13), we evaluated a sample of oncology outpatients who were experiencing pain from bone metastasis for gender differences in baseline pain. One hundred thirty-three women and 65 men were enrolled in Correspondence to: Christine Miaskowski, RN, PhD, FAAN, Department of Physiological Nursing, University of California, 2 Koret Way, Box 0610-N631Y, San Francisco, CA ( chris.miaskowski@nursing.ucsf.edu). DOI: /jncimonographs/lgh024 Journal of the National Cancer Institute Monographs, No. 32, Oxford University Press 2004, all rights reserved. Journal of the National Cancer Institute Monographs No. 32,

2 Table 1. Gender differences in cancer-related pain Author, date, and study design (Ref) Patient population and sample size Pain variable Findings related to gender differences Cleeland et al., 1994 (9) Oncology outpatients with metastatic cancer (n 1308) Treatment of pain Women were 1.5 times as likely to be undertreated for their cancer pain. Descriptive study (secondary analysis of data from a RCT designed to test an intervention to improve cancer pain management) from bone metastasis (n 109) No gender differences were found in any of the pain intensity measures (i.e., pain right now, average pain, worst pain, least pain) that were evaluated using 0 10 numeric rating scales. Descriptive, cross sectional study No gender differences were found in any of the pain intensity measures (i.e., pain right now, average pain, worst pain, least pain) that were evaluated using 0 10 numeric rating scales. Turk and Okifuji, 1999 (10) Descriptive, retrospective study RCT randomized clinical trial. Cancer patients referred for treatment of pain at a comprehensive cancer center (n 143) this randomized clinical trial. All patients were experiencing pain from bone metastasis. At baseline, no gender differences were found in any of the pain intensity measures (i.e., pain right now, average pain, worst pain, least pain) that were evaluated using 0 10 numeric rating scales. An examination of unpublished data from a descriptive, cross-sectional study of oncology outpatients who were receiving active treatment for their cancer (n 117) revealed that 50 patients (42.7%) were experiencing cancer pain. No gender differences were found in any of the pain intensity measures (i.e., pain right now, average pain, worst pain, least pain) that were evaluated using 0 10 numeric rating scales. Only one published (10) and two unpublished studies (Miaskowski et al.) have provided data on gender differences in pain severity in patients with chronic cancer pain. The findings from these three studies indicate that men and women report similar levels of pain intensity when they experience chronic cancer pain. Additional research is warranted to determine whether this finding persists with different types of chronic cancer pain as well as with acute cancer-related pain. The finding of a gender bias in the treatment of cancer pain (9) requires additional investigation. If this gender bias of undertreatment of women, which has been reported in another study of chronic pain (14), is found in future research, it has tremendous clinical implications for the effective management of cancer-related pain as well as for additional research on the reasons why this bias exists. GENDER DIFFERENCES IN CANCER-RELATED FATIGUE No gender differences were found in pain severity measured using the Multidimensional Pain Inventory Scale Fatigue is a common symptom experienced by patients with cancer as well as by cancer survivors (15 19). However, only eight published (20 27) and two unpublished studies (Miaskowski et al.) have evaluated for gender differences in cancerrelated fatigue. Findings from these 10 studies are summarized in Table 2. Two studies (21,27) evaluated the prevalence of fatigue in two different patient populations (i.e., patients with lung cancer who were receiving radiation therapy and inpatients and outpatients referred for palliative care) and found no gender differences in the prevalence of fatigue. The remaining eight descriptive, cross-sectional studies evaluated for gender differences in fatigue severity. In three of the studies that evaluated oncology outpatients who were receiving chemotherapy or radiation therapy (22,25,26), women reported higher fatigue severity scores than men. Similar findings were reported in one study that evaluated for gender differences in fatigue severity in patients following allogeneic bone marrow transplantation (24). In the one unpublished study (Miaskowski et al.) that evaluated for gender differences in fatigue severity in oncology outpatients who were receiving active treatment, no differences were found. Likewise, in the studies that evaluated for gender differences in fatigue severity in patients admitted to a palliative care unit (23) or in patients with chronic pain from bone metastasis, no differences were found. In addition, in the one study that evaluated patients who were off treatment for at least 6 months (20), no differences in fatigue severity were found between men and women. Given the high prevalence of fatigue in the cancer patient population, as well as across the disease trajectory, the number of studies that have evaluated for gender differences in the prevalence and severity of fatigue is extremely small. To date, the heterogeneous nature of the patient populations in these studies makes it difficult to draw any conclusions about whether gender differences in the prevalence and severity of cancerrelated fatigue exist, what the reasons are for these differences, or the effect of these differences on patients lives. An important consideration that should be noted as this area of research moves forward is that one study done in a primary care setting found that women reported higher fatigue severity scores than men (28). In addition, a number of investigators have noted that women, in general, report higher rates of symptoms than men (29 30). Therefore, although additional research is warranted on gender differences in fatigue, both in adults and children with cancer, these types of studies may have to include appropriate comparison groups to draw definitive conclusions given the high levels of fatigue that are reported in the general population. Additional research areas related to gender differences in 140 Journal of the National Cancer Institute Monographs No. 32, 2004

3 Table 2. Gender differences in cancer-related fatigue Author, date, and study design (Ref) Patient population and sample size Fatigue variable Findings related to gender differences Akechi et al., 1999 (22) Heinonen et al., 2001 (24) Hickok et al., 1996 (21) Miaskowski et al. (unpublished data) Descriptive study (secondary analysis of data from a RCT designed to improve cancer pain management) Miaskowski et al. (unpublished data) Pater et al., 1997 (26) Redeker et al., 2000 (25) Servaes et al., 2000 (20) Descriptive study Stone et al., 1999 (23) Prospective, controlled, crosssectional study Walsh et al., 2000 (27) Heterogeneous sample of oncology outpatients (N 445) Allogeneic bone marrow transplant recipients (n 109) Lung cancer patients receiving RT (n 50) from bone metastasis (n 198) Heterogeneous group of patients receiving CTX or RT (n 2390) Heterogeneous sample of cancer patients who were undergoing CTX (n 263) Heterogeneous sample of disease free cancer patients (i.e., off treatment for at least 6 mo) (n 85) Inpatients with advanced cancer who were admitted for palliative care (n 95 patients and 98 controls) Oncology inpatients and outpatients who were referred to a palliative medicine program (n 1000) cancer-related fatigue include the need to systematically investigate for changes in the prevalence and severity of fatigue across the disease trajectory, the need for longitudinal studies of gender differences in fatigue severity across different treatment regimens, the need to investigate how gender role functioning might influence the development of cancer-related fatigue, and the need to evaluate for gender differences in the effectiveness of interventions to manage cancer-related fatigue. GENDER DIFFERENCES IN CANCER-RELATED DEPRESSION Univariate analysis no gender differences in fatigue severity measured using the fatigue subscale of the POMS. Multivariate analysis female gender was associated with higher fatigue scores on the fatigue subscale of the POMS. Women reported higher fatigue scores than men on the fatigue subscale of the POMS. fatigue measured using the fatigue subscale of the POMS. measured using the Lee Fatigue Scale. Women had higher fatigue scores than men using the QLQ-C30. Women reported higher fatigue scores than men using the single fatigue item from the Symptom Distress Scale. as measured by the Checklist of Individual Strength. using the Fatigue Scale. fatigue. CTX chemotherapy; POMS Profile of Mood States; QLQ-C30 Quality of Life Questionnaire-Cancer; RT radiation therapy; RCT randomized clinical trial. Like pain and fatigue, depression is frequently underdiagnosed in patients with cancer, and therefore it is frequently undertreated (31 34). In addition, data from epidemiologic studies of depression consistently report a higher prevalence rate of depressive symptoms among women compared with men (35 37). However, only seven published (25,27,38 42) and two unpublished studies (Miaskowski et al.) from our group were identified that evaluated for gender differences in the prevalence or severity of depression in patients with cancer. The findings from these nine studies are summarized in Table 3. Five of the nine studies evaluated for gender differences in the prevalence of depression (27,38 40,42). One study evaluated a cross-sectional sample of inpatients and outpatients who were receiving cancer treatment (38), two studies evaluated patients who were receiving palliative care (27,39), one longitudinal study evaluated patients with lung cancer (42), and one longitudinal study evaluated patients with head and neck cancer (40). Three of the five prevalence studies found no gender differences in depression rates (27,38 39). The other two studies (40,42) reported higher prevalence rates of depression in women. Only two published studies (25,41) and two unpublished studies from our own group evaluated for gender differences in the severity of depressive symptoms. Given and colleagues (41) evaluated for gender differences in the severity of depression in oncology outpatients who were 50 years of age or older and who were receiving active treatment for cancer. They found an interaction between age and gender on the level of depression measured using the Center for Epidemiological Studies Depression scale (CES-D). For men, as age increased by 1 year, depression decreased by 0.33 units; whereas for women, as age increased by 1 year, depression increased by 0.16 units. In a descriptive, cross-sectional study of oncology outpatients who were receiving chemotherapy, Redeker and colleagues (25) found no gender differences in the severity of depression using the Profile of Mood States. Likewise, in our Journal of the National Cancer Institute Monographs No. 32,

4 Table 3. Gender differences in cancer-related depression Author, date, and study design (Ref) Patient population and sample size Depression variable Findings related to gender differences Aass et al., 1997 (38) Ciaramella and Poli, 2001 (39) Descriptive study de Leeuw et al., 2001 (40) Prospective, descriptive, longitudinal study Given et al., 1994 (41) Hopwood et al., 2000 (42) Descriptive study (secondary analysis of data from a RCT designed to improve cancer pain management) Redeker et al (25) Walsh et al., 2000 (27) Inpatients and outpatients who were receiving CTX or RT (n 716) Cancer patients who were recruited from the Pain Therapy and Palliative Care Unit (n 100) Patients who completed treatment for head and neck cancer were evaluated at 6 mo and 1, 2, and 3 y (n 123 to 197) Oncology outpatients, 50 years of age or older, who were receiving active treatment (n 111) Lung cancer patients who participated in one of three multicenter randomized clinical trials (n 1189) from bone metastasis (n 198) Heterogeneous sample of cancer patients who were undergoing CTX (n 263) Oncology inpatients and outpatients who were referred to a Palliative Medicine Program (n 1000) study of oncology outpatients who were experiencing pain from bone metastasis (Miaskowski et al.), no gender differences in the severity of depression were found at baseline using the Profile of Mood States. In addition, in our cross-sectional study of oncology outpatients who were receiving active treatment for their cancer (Miaskowski et al.), no gender differences were found in the severity of depressive symptoms measured using the CES-D. Because of the limited amount of evidence, it is impossible to draw definitive conclusions regarding gender differences in the prevalence or severity of depression in patients with cancer. As stated previously, findings from population-based studies indicate that the prevalence rates for depression are higher in women (35 37). However, these findings need to be placed within the context that women are more likely to express their feelings and report more symptoms than men (30). Another factor that needs to be considered in this area of scientific inquiry is whether the gender differences that were reported in previous studies are an artifact of the measurement procedures. In an excellent paper, Stommel and colleagues (43) reported findings from a confirmatory factor analysis that identified two items on the CES-D that produced biased responses when comparisons were done of men s and women s responses to these items. Specifically, men, who otherwise had the same level of depressive symptoms as women, were less likely to have crying spells. In contrast, the gender bias in response to the item talked less was in the opposite direction; namely, men with depressive symptoms were more likely to reduce their verbal communication compared with women with the same level of depressive symptoms. The authors recommended that these items be removed from any analysis of gender differences in depressive symptoms using the CES-D. CONCLUSIONS No gender differences in the prevalence rate for depression that was measured using the HADS. No gender difference in the prevalence rates for depression using the Structured Clinical Interview for the DSM-IIIR, the interview criteria for major depression modified by Endicott for cancer patients, and the Hamilton Depression Rating Scale. Higher prevalence of depression in women compared to men using the CES-D. An interaction between age and gender on level of depression was found when depression was measured using the CES-D. For men, as age increased by one year, depression decreased by 0.33 units. For women, as age increased by one year, depression increased by 0.16 units. rates for depression (measured using the HADS) increased in female patients compared with male patients in patients with good performance status. The gender difference in depression disappeared as performance status worsened. depression measured using the depression subscale of the POMS depression measured using the CES-D. depression measured using the depression subscale of the POMS. depression. CES-D Center for Epidemiologic Studies-Depression Scale; CTX chemotherapy; HADS Hospital Anxiety and Depression Scale; POMS Profile of Mood States; RT radiation therapy; RCT randomized clinical trial. Research studies on gender differences in cancer-related pain, fatigue, and depression are minimal in number, are restricted to studies of differences in prevalence rates and severity scores, and have for the most part yielded conflicting results. Additional investigations are warranted to determine whether the gender differences in prevalence rates and severity of these symptoms represent clinically meaningful differences. If these gender differences are substantiated, these findings will guide the design of studies to elucidate the underlying mechanisms for these differences, as well as the development and testing of gender-specific interventions to treat cancer-related pain, fatigue, and depression. 142 Journal of the National Cancer Institute Monographs No. 32, 2004

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