Abstract
Objective:
Physical activity may mitigate the effects of cancer treatment. We sought to evaluate the association between self-reported physical activity, neuropathy symptomatology, and emotional health in gynecologic cancer survivors.
Methods:
Patients were recruited from an academic gynecologic oncology practice to a prospective cohort study. Participants completed semiannual surveys on quality of life (QOL), neuropathy symptoms, depression, distress, and health behaviors. Abstracted clinical data included cancer type, FIGO stage at diagnosis and treatments received (chemotherapy, surgery, radiation). Physical activity [no: moderate physical activity <150 min/week, yes: ≤150 min/week] and neuropathy symptomatology [high (FACT/GOG-Ntx ≥11; upper quartile); low (<11)] were dichotomized. Linear regression models assessed the associations between physical activity, neuropathy and psychosocial outcomes.
Results:
A total of 194 participants were included in this analysis. We identified significant interactions between physical activity and neuropathy in the depression (p=0.0006) and QOL (p=0.007) models. Greater physical activity and lower neuropathy scores were independently associated with fewer depressive symptoms (p=0.02 and p<0.0001, respectively) and greater QOL (p=0.005 and p<0.0001). Low neuropathy scores were associated with lower distress (p<0.0001). Women with high neuropathy scores had larger beneficial associations between being physically active and depression and QOL. In the distress model, interaction between neuropathy and physical activity was suggested (p=0.05).
Conclusions:
Physical activity was associated with favorable psychosocial outcomes in gynecologic cancer survivors, most notably among those with worse neuropathy. These data suggest consideration of prescriptive exercise should be evaluated as a means of mitigating cancer-associated neuropathies and their effect on emotional health.
Introduction
Diagnosis and management of treatment-related side effects has become increasingly important as the population of long-term gynecologic cancer survivors continues to grow. Current estimates suggest there are over 1.2 million survivors of gynecologic cancer living in the United States, with another 110,070 new cases diagnosed annually (1). The increasing survival of gynecologic cancer patients highlights the importance of prevention and mitigation of treatment-related side effects for survivors of gynecologic cancer.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and well-recognized treatment side-effect with significant (≥grade 2) neuropathy affecting up to 36% of older ovarian cancer patients and 20% of patients under the age of 70 following treatment with commonly used chemotherapeutic agents (2,3). Furthermore, literature suggests significant under-reporting of CIPN, possibly owing to limited tools for both qualitative and quantitative assessment of patients’ symptoms (4). Unfortunately to date no effective prevention strategy has been identified, and pharmacologic treatment of established CIPN has been largely unsuccessful(5,6). Not only does CIPN negatively affect quality of life (QOU), but it can also lead to discontinuation of therapy and poor outcomes associated with failure to complete treatment, along with increased risk for falls (6).
In recent years, literature on the benefits of physical activity for cancer survivors, across diagnoses, has significantly expanded (7–11). This includes evidence that physical activity is associated with better health-related QOU, and less pain, fatigue, insomnia and emotional distress among endometrial and ovarian cancer survivors, (8) and evidence that physical activity may be associated with improved CIPN symptomatology in individuals with cancer (12–14). Our objective was to evaluate the association between self-reported physical activity and neuropathy symptomatology and their combined associations with QOL, distress, and depression in a cohort of gynecologic cancer survivors.
Methods:
Study Design
English-speaking, female adults aged 18 years and older with a history of a gynecologic cancer (ovarian, uterine, cervical, vaginal or vulvar cancer) were recruited from the University of Minnesota into the Gynecologic Oncology: Life after Diagnosis (GOLD) study. Detailed methods of this prospective cohort study are described elsewhere (15). All participants signed written informed consent prior to enrollment, and the study received approval from the University of Minnesota Institutional Review Board (# 1612S01581).
Recruitment
Participants were recruited via scheduled clinic appointments or mail March 2017 through March 2020. Time since diagnosis or treatment was not an eligibility criterion, though the majority of patients have been recruited while in surveillance. At the time of analysis (November 2019), 442 participants had enrolled in the GOLD study.
Data collection and study measures
Participants completed a baseline survey at initial study recruitment and semiannual surveys evaluating numerous potential concerns following a cancer diagnosis. Data relevant to this analysis were collected at baseline (physical activity, demographic and clinical confounders used in the multivariate analysis) and the 6-month survey (psychosocial and QOL outcomes, and neuropathy, the latter added to the 6-month survey in October 2018). Self-reported neuropathy symptomatology was assessed using the validated FACT/GOG-Ntx subscale (16). Physical activity was self-reported in minutes of moderate and vigorous activity per week. Cancer-related-QOL was measured using the Functional Assessment of Cancer Therapy – General (FACT-G) (17) and emotional health including depression and distress were measured using the PHQ-8 (18) and National Comprehensive Cancer Network NCCN - distress thermometer (19), respectively. Abstracted clinical data from the electronic health record included cancer type, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, and treatments received (chemotherapy, surgery, and/or radiation).
Statistical Analysis
At the time of analysis, 408 participants had completed the baseline survey and 302 had completed the 6-month survey. Data analysis was limited to those who completed both the physical activity survey at baseline and neuropathy FACT/GOG-Ntx subscale at 6 months (N=194). For this analysis, self-reported physical activity was dichotomized based on the recommendations of the Health and Human Services (HHS) Physical Activity Guidelines for Americans, defining <150 min of moderate or vigorous physical activity as “no”, and ≥150 min of moderate or vigorous physical activity per week as “yes” (20). There is no established “cutoff’ neuropathy score to suggest significant or clinically relevant neuropathy symptoms on the FACT/GOG-Ntx subscale. Therefore, we used the upper quartile score for our sample population to define “high” neuropathy symptomatology [high (≥11 points; upper quartile); low (<11 points)]. Since physical activity was measured at baseline (and not at 6 months as our main outcomes of interest and neuropathy), a sensitivity analysis was conducted to compare the physical activity measures collected at the year 1 survey with those at baseline to ascertain the consistency of the physical activity measures over time (concordant pairs of meeting / not meeting physical activity recommendations).
Pearson’s chi-squared tests were used to compare clinical and demographic characteristics by high and low neuropathy symptomology. To examine the associations between physical activity and neuropathy and psychosocial outcomes (QOL, depression, distress), linear regression models were conducted, adjusting for age at survey baseline (years), body mass index (BMI, kg/m2, continuous), treatment with chemotherapy (yes/no), stage at diagnosis (early stage I and II/advanced stage III and IV), history of diabetes (yes/no), and annual household income (<$50,000/$50,000-$99,999/≥$100,000/prefer not to answer). Missing data were minimal; participants with missing values were removed from the analysis. Statistical analysis was performed using SAS version 9.4 software (SAS Institute Inc., Cary, NC, USA), and p-values less than 0.05 were considered statistically significant. Figure 1 was generated using R-packages ggplot2, gridExtra, and ggpubr.
Figure 1.
Visualized interaction between neuropathy and physical activity in relation to QOL, Depression, and Distress, N=194.
* The visualized average scores represent women with mean covariate values in the study population (age 61, BMI 30, no diabetes), and diagnosed with ovarian cancer, advanced stage, and having received chemotherapy. Individuals with other covariate values would have different intercepts, but the estimated slopes of the regression lines would be the same.
Results:
A total of 194 participants were included in this analysis. Participants with low (score <11) and high (score ≥ 11) neuropathy symptomatology differed by cancer stage (stage III/IV: 31.2% vs. 55.4%; p=0.001), gynecologic cancer type (ovarian: 29.7% vs. 54.6%; endometrial: 54.7% vs. 36.4%; p=0.009), diagnosis of diabetes (8.1% vs. 18.2%; p=0.04) and treatment with chemotherapy (49.2% vs. 83.3%; p<0.0001; Table 1). Other differences between participants with low and high neuropathy symptoms with respect to clinical and demographic factors did not reach statistical significance, including time since diagnosis and treatment status. Of note, there was no statistically significant difference in the proportion of participants meeting recommended physical activity guidelines (≥150 min of moderate or vigorous physical activity per week) between participants with low (60.9%) and high (59.1%) neuropathy symptoms (p=0.80).
Table 1.
Participants demographic and clinical characteristics by neuropathy score (FACT/GOG-Ntx <11 vs. 11+), N=194.
| Neuropathy score <11 | Neuropathy score 11+ | ||||
|---|---|---|---|---|---|
| Variable | N | % | N | % | P-value |
| Age at baseline (years) | 0.08 | ||||
| <50 | 25 | 19.5 | 5 | 7.6 | |
| 50-59 | 34 | 26.6 | 15 | 22.7 | |
| 60-69 | 54 | 42.2 | 33 | 50.0 | |
| 70-79 | 15 | 11.7 | 13 | 19.7 | |
| Race | 0.98 | ||||
| White, Non-Hispanic | 126 | 98.4 | 1 | 1.5 | |
| Other | 2 | 1.6 | 65 | 98.5 | |
| Education | 0.71 | ||||
| No college degree | 78 | 60.9 | 42 | 63.6 | |
| At least college degree | 50 | 39.1 | 24 | 36.4 | |
| Marital Status | 0.82 | ||||
| Never married | |||||
| Widowed/Divorced | 51 | 40.2 | 25 | 38.5 | |
| Married/Partnered | 76 | 59.8 | 40 | 61.5 | |
| Income | 0.08 | ||||
| <$50K | 41 | 32 | 26 | 40.0 | |
| $50K-99K | 39 | 30.5 | 23 | 35.4 | |
| ≥$100K | 37 | 28.9 | 8 | 12.3 | |
| Prefer not to say | 11 | 8.6 | 8 | 12.3 | |
| Employment | 0.08 | ||||
| Yes – full or part time | 78 | 60.9 | 29 | 43.9 | |
| No | 12 | 9.4 | 8 | 12.1 | |
| Retired | 38 | 29.7 | 29 | 43.9 | |
| Urban/rural residence | 0.50 | ||||
| Urban | 110 | 85.9 | 59 | 89.4 | |
| Rural | 18 | 14.1 | 7 | 10.6 | |
| Physical activity (at baseline) | 0.80 | ||||
| <150 minutes per week | 50 | 39.1 | 27 | 40.9 | |
| 150+ minutes per week | 78 | 60.9 | 39 | 59.1 | |
| Time since diagnosis | 0.47 | ||||
| < 1 year | 9 | 7.0 | 9 | 13.6 | |
| 1-<2 years | 54 | 42.2 | 24 | 36.4 | |
| 2-<5 years | 62 | 48.4 | 31 | 47.0 | |
| ≥5 years | 3 | 2.3 | 2 | 3.0 | |
| Cancer Type | 0.009 | ||||
| Ovarian | 38 | 29.7 | 36 | 54.6 | |
| Cervical | 15 | 11.7 | 5 | 7.6 | |
| Endometrial | 70 | 54.7 | 24 | 36.4 | |
| Vaginal/Vulvar | 5 | 3.9 | 1 | 1.5 | |
| Cancer Stage (at baseline) | 0.001 | ||||
| I or II | 86 | 68.8 | 29 | 44.6 | |
| III or IV | 39 | 31.2 | 36 | 55.4 | |
| Diabetes | 0.04 | ||||
| No | 114 | 91.9 | 54 | 81.8 | |
| Yes | 10 | 8.1 | 12 | 18.2 | |
| Surgery | 0.68 | ||||
| No | 6 | 4.7 | 4 | 6.1 | |
| Yes | 122 | 95.3 | 62 | 93.9 | |
| Chemotherapy | <0.0001 | ||||
| No | 65 | 50.8 | 11 | 16.7 | |
| Yes | 63 | 49.2 | 55 | 83.3 | |
| Radiation | 0.25 | ||||
| No | 91 | 71.1 | 52 | 78.8 | |
| Yes | 37 | 28.9 | 14 | 21.2 | |
Meeting physical activity recommendations and lower neuropathy scores were associated with participants reporting better QOL, and lower depression and distress symptoms (Table 2). In the multivariate regression models, there was evidence of significant interactions between physical activity and neuropathy in the depression (p=0.0006) and QOL (p=0.007) models (Table 3). These interactions indicated greater beneficial associations of being physically active with depressive symptoms and QOL in women who had high neuropathy scores than in women with low neuropathy scores. The estimated benefits of being physically active (compared with not being physically active) on the outcomes of interest in women with low neuropathy scores were small and not statistically significant. In the distress model, the interaction between neuropathy and physical activity did not quite reach statistical significance (p=0.05), however, the results were in the same direction with physical activity being associated with greater benefit in the presence of high neuropathy.
Table 2.
Mean psychosocial outcome scores by neuropathy symptomology (FACT/GOG-Ntx <11 vs. 11+) and physical activity levels, N=194.
| Outcome scores | Not physically active | Physically active | P-value | |||
|---|---|---|---|---|---|---|
| N | Mean (SD) | N | Mean (SD) | |||
| Neuropathy score <11 | Distress Thermometer | 46 | 2.00 (2.37) | 73 | 1.75 (2.16) | 0.56 |
| Depression (PHQ-8) | 50 | 3.06 (3.67) | 78 | 2.40 (2.61) | 0.24 | |
| FACT QOL | 50 | 86.96 (14.54) | 78 | 90.08 (13.49) | 0.22 | |
| Neuropathy score 11+ | Distress Thermometer | 26 | 4.46 (2.79) | 35 | 3.06 (3.01) | 0.07 |
| Depression (PHQ-8) | 27 | 8.56 (5.87) | 38 | 3.76 (3.68) | 0.0001 | |
| FACT QOL | 27 | 70.17 (17.08) | 38 | 83.32 (13.45) | 0.0009 | |
Table 3.
Multivariate linear regression models exploring psychosocial outcomes by neuropathy symptomology (FACT/GOG-Ntx <11 vs. 11+) and physical activity levels, N=194.
| Parameter | Estimate (95% CI)* | P-value | |
|---|---|---|---|
| Distress Thermometer | Physically Active (vs. Not Physically active) | 0.03 (−0.92, 0.98) | 0.95 |
| Neuropathy score 11+ (vs. <11) | 2.63 (1.40, 3.87) | <0.0001 | |
| Interaction Physically Active* Neuropathy score 11+ | −1.54 (−3.06, −0.03) | 0.05 | |
| Depression (PHQ-8) | Physically Active (vs. Not Physically active) | −0.17 (−1.52, 1.18) | 0.80 |
| Neuropathy score 11+ (vs. <11) | 4.95 (3.18, 6.73) | <0.0001 | |
| Interaction Physically Active* Neuropathy score 11+ | −3.85 (−6.03, −1.66) | 0.0006 | |
| FACT QOL | Physically Active (vs. Not Physically active) | 1.57 (−3.70, 6.84) | 0.56 |
| Neuropathy score 11+ (vs. <11) | −17.30 (−24.23, −10.38) | <0.0001 | |
| Interaction Physically Active* Neuropathy score 11+ | 11.79 (3.25, 20.33) | 0.007 |
Model adjusted for age at baseline, body mass index, annual household income, diabetes, chemotherapy, cancer stage, and disease location.
Figure 1 visualizes the modeled interaction patterns using a hypothetical individual in our study population: a woman with mean covariate values based on our study population (BMI 30, age 61, no diabetes), with advanced ovarian cancer, and treated with chemotherapy. The visualization depicts our adjusted model QOL, depression, and distress score estimates with and without interaction. In the model with interaction, the estimated benefit associated with being physically active is greater in the presence of high neuropathy symptoms, as depicted by a steeper slope, than the estimated average benefit across all women from the non-interaction model; whereas if neuropathy symptoms are low, the estimated benefit of being physically active is smaller (flatter slope) than the estimated average benefit across all women in the non-interaction model.
We conducted numerous sub-group analyses (women who did vs. those who did not receive chemotherapy; women aged ≤60 vs. >60 years at the time of survey) to ensure the relationships were consistent. Physical activity was associated with greater differences in emotional health among those with high neuropathy symptoms with the exception of younger women where neither physical activity nor neuropathy was associated with depression scores.
Discussion:
We found a favorable association between being physically active and psychosocial health however, on further investigation accounting for possible interaction, we found a strong beneficial association between being physically active and psychosocial health primarily among women with high neuropathy symptomatology. Our findings suggest that certain subgroups of gynecologic cancer survivors might benefit more than others from meeting physical activity guidelines. This study adds to a growing body of literature that suggests non-pharmacologic methods may be effective for improving the QOL of cancer survivors with neuropathy(21). This also emphasizes the need for prospective studies of exercise interventions to prevent and manage symptoms of neuropathy that also address QOL and to gain a more thorough understanding of who is most likely to benefit from additional promotion of physical activity after a cancer diagnosis.
Despite the potential benefits associated with physical activity during and after cancer treatment (22), many oncologists do not routinely prescribe physical activity to patients, and gynecologic cancer survivors historically have not met physical activity guidelines (23). One study found that less than 40% of gynecologic cancer survivors were exercising at least 150 minutes per week (24). Additionally, an international survey-based study among practicing oncologists noted that less than half of oncologists regularly promoted physical activity to patients (25). Importantly, “lack of time’’ was cited as the greatest barrier to promoting physical activity by oncologists (25). Knowing which patients may benefit more from counseling on physical activity is crucial as the oncologic patient population and demands of patient care increase. Our study suggests that gynecologic cancer patients reporting higher neuropathy symptoms might especially benefit from counseling on physical activity.
Our study is strengthened by the inclusion of patients with all types of gynecologic cancer, as well as those who did and did not receive chemotherapy, however, our study also has limitations. As with all survey-based studies, there is the potential for response bias. Compared with study participants, non-responders (to the 6-month survey compared to baseline) were slightly younger, less likely to be non-Hispanic white, more likely to have cervical and more advanced cancer, and less likely to have received surgery and to be physically active. Since physical activity was measured at baseline, while neuropathy symptomatology and outcomes were measured at 6 months, we made the assumption that physical activity patterns did not change significantly in 6 months. In a sensitivity analysis comparing physical activity at baseline and the 1 - year-follow-up in a subset of participants, 70% of participants had concordant answers with regards to physical activity, and we assume that this fraction would have been greater had we measured physical activity at 6 months, suggesting we have relatively low misclassification. Given the observational nature of this study, we cannot establish that our estimated associations are causal. Also, we did not have baseline data regarding neuropathy symptoms (prior to cancer diagnosis and treatment) and therefore we could not ascertain whether participants’ neuropathy symptoms developed as a result of their cancer or cancer treatment. Similarly, it is also not known if participants’ neuropathy symptoms had an effect on their physical activity level. In addition, neuropathy is difficult to reliably quantify; a systematic review and meta-analysis performed by Cliff et al. noted that studies often evaluate different neuropathy outcomes and degrees of neuropathy. We chose the FACT-GOG/Ntx subscale which is both simple to use and validated; however there is no standardized, “severe” neuropathy cut-off score for this specific scale that correlates with commonly used clinical grading instruments (14,15). Finally, as a Minnesota-based study, participants were mostly White, meaning the results may not be generalizable to broader population.
Physical activity was associated with favorable psychosocial outcomes in gynecologic cancer survivors, particularly among those with higher neuropathy symptoms. Building on the findings from our observational study, future randomized controlled trials are needed to further validate the efficacy of exercise-based interventions for prevention and treatment of neuropathy in women specifically with gynecologic cancers, particularly among a more diverse population. Future work should also evaluate potential differences in the effect of physical activity on QOL in the presence versus absence of neuropathy as suggested in this study. We also advocate for future studies in gynecologic cancer survivors to better assess and define neuropathy symptoms on self-reported scales to enhance risk stratification and maximize QOL for these patients.
Highlights:
Gynecologic cancer survivors who meet physical activity recommendations have superior psychosocial outcomes.
Lower neuropathy symptomatology is independently associated with greater quality of life and fewer depressive symptoms.
Survivors with neuropathy derive the most benefit in quality of life and depression from being physically active.
Acknowledgments
Funding: This work was supported by the National Institutes of Health (P30 CA77598, UL1TR002494) and the Masonic Cancer Center.
Footnotes
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Conflicts of interest: None
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