Dietary quality and chemotherapy-induced peripheral neuropathy in colon cancer

Abstract

Introduction:

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting chemotoxicity caused by oxaliplatin. This study investigated the relationship between dietary quality and the development of moderate and/or severe CIPN in colon cancer survivors using data from the Focus on Reducing Dose-limiting Toxicities in Colon Cancer with Resistance Exercise (FORCE) trial.

Methods:

Diet quality was collected using a 127-item food frequency questionnaire and scored using the Alternative Healthy Eating Index-2010 (AHEI-2010). CIPN was assessed with the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) at each chemotherapy cycle. The association of dietary quality with time to first moderate-to-severe (moderate-severe) or severe event of CIPN was estimated using Cox proportional hazards models. Only participants receiving oxaliplatin were included in this analysis (n=132).

Results:

Seventy-four participants (56.1%) reported moderate-severe CIPN. Higher dietary quality was associated with a significantly decreased risk of moderate-severe CIPN [Hazard Ratio (HR): 0.96, 95% CI: 0.93, 0.99] and severe CIPN [HR: 0.91 (95% CI: 0.85, 0.98)]. Consumption of red and processed meat [HR: 1.78 (95% CI: 1.07, 2.83)] and sugar-sweetened beverages [HR: 1.33 (95% CI: 1.10, 1.59)] was associated with increased risk of moderate-severe CIPN. Consumption of sugar-sweetened beverages was associated with increased risk of severe CIPN [HR: 1.57 (95% CI: 1.14, 2.18)], whereas vegetable consumption was associated with reduced risk of severe CIPN [HR: 0.29 (95% CI: 0.09, 0.73)].

Conclusion:

Among patients with colon cancer receiving oxaliplatin-based chemotherapy, higher baseline dietary quality was associated with a reduced risk of moderate-to-severe CIPN.

Précis:

Chemotherapy-induced peripheral neuropathy is a common and dose-limiting chemotoxicity caused by oxaliplatin. In this cohort analysis nested within a randomized control trial of 132 colon cancer survivors receiving oxaliplatin, higher dietary quality was associated with a significantly lower risk of moderate and/or severe chemotherapy-induced peripheral neuropathy.

INTRODUCTION

Oxaliplatin-based chemotherapy remains a standard-of-care in patients with surgically resected high-risk colon cancer.¹ Platinum-based chemotherapy causes acute and chronic chemotherapy-induced peripheral neuropathy (CIPN),^2–4 and 85% of patients with colon cancer experience CIPN after the first treatment cycle of oxaliplatin.⁵ Experiencing CIPN in early treatment cycles increases the likelihood of developing chronic neurotoxicity that persists beyond the cessation of treatment.⁵ Moderate or severe CIPN results in chemotherapy dose delays, reductions, or discontinuation of oxaliplatin.^6,7 A reduction in chemotherapy dose intensity is associated with decreased disease-free and overall survival.^8,9 Identifying modifiable risk factors associated with CIPN may be a valuable target for patient counseling and behavior change programs.

Patients are often interested in nutrition following a cancer diagnosis, and many are motivated to modify their dietary intake.^10–13 Dietary patterns quantify the habitual consumption of food combinations, quantities, and variety.¹⁴ Dietary patterns are more clinically and biologically relevant than single nutrients.¹⁵ Dietary patterns during and after chemotherapy are associated with disease-free and overall survival in patients with colon cancer.^16–18 Research on the relationship between nutrition and CIPN has predominately focused on the influence of individual vitamins, minerals, and nutrients.⁶ Emerging evidence suggests that diet quality may help reduce the risk and severity of CIPN among patients who receive platinum-based chemotherapies.¹⁹ However, whether dietary quality relates to time to develop CIPN is unknown. This analysis tested the hypothesis that dietary pattern is associated with the hazard rate of developing CIPN, using data from the Focus on Reducing Dose-limiting Toxicities in Colon Cancer with Resistance Exercise (FORCE) trial.²⁰

METHODS

The FORCE trial used a randomized, parallel-group design to examine the effect of resistance exercise versus non-exercise control on the co-primary endpoints of chemotherapy relative dose intensity (RDI) and patient-reported chemotoxicities. The FORCE trial was conducted at three centers in the United States: Kaiser Permanente Northern California (Oakland, CA), Dana-Farber Cancer Institute (Boston, MA), and Penn State Cancer Institute (Hershey, PA). The Institutional Review Board at all sites approved the study protocol. The study followed Good Clinical Practice and ethical principles in the Declaration of Helsinki. The study was registered on ClinicalTrials.gov as NCT03291951. The trial design and primary outcomes are described elsewhere.^20,21 Briefly, home-based, progressive resistance training did not improve the chemotherapy RDI or reduce the average number of moderate-severe patient-reported chemotoxicities per week compared to usual care control.²⁰

Patient population

Eligible participants were adults (≥18 years old) with stage II and III colon cancer who were enrolled in the FORCE trial and received oxaliplatin as part of their treatment regimen. Participants had completed curative-intent surgical resection and planned to initiate postoperative chemotherapy. Participants were eligible until they received their second cycle of chemotherapy. Eligible participants were not concurrently treated for other cancers (except non-melanoma skin cancer, in situ cervical cancer, or localized prostate cancer treated with surveillance only). Additional eligibility criteria and recruitment methods have been previously described.²¹ All participants provided informed consent and physician approval before completing any study measures.

Assessment of Dietary Intake and Diet Quality

At baseline (before randomization), participants completed the validated semi-quantitative 2014 Block Food Frequency Questionnaire (FFQ) to assess dietary intake.²² This 127-item FFQ assessed the intake of foods and beverages over the past month. Participants were prompted to report food consumption based on frequency (ranging from “never” to “every day”) and quantity using portion size pictures or common serving measures (i.e., units or household measurements). Participants who were missing baseline dietary assessment were excluded from the analysis.

Food and nutrient components from the FFQ were used to calculate diet quality using the Alternative Healthy Eating Index-2010 (AHEI-2010).²³ The AHEI-2010 was selected because it places additional emphasis on foods and nutrients associated with chronic disease risk, including cardiovascular disease and cancer incidence.^23,24 The AHEI-2010 includes 11 components as standard servings per day, with four components (sugar-sweetened beverages, red/processed meat, trans fat, and sodium) scored negatively (i.e. higher consumption results in lower score). Whole-grains and alcohol are scored on sex-specific intakes. Sodium is scored as lowest and highest decile. Component scores are summed to obtain the overall diet quality score from 0-110, with higher AHEI-2010 scores representing higher diet quality. The food and beverage components and units for AHEI-2010 are shown in Table S1.

Patient-reported neuropathy

CIPN was assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).²⁵ PRO-CTCAE scores (e.g., “moderate”) for adverse events correspond to those reported by the clinician assessed Common Terminology Criteria for Adverse Events (CTCAE).²⁵ Participants completed the PRO-CTCAE at each treatment cycle after enrollment. Participants reported the severity and degree to which CIPN interfered with daily activities over the previous seven days. Severity of CIPN at each cycle (i.e. none, mild, moderate, or severe) was graded using a validated composite graded algorithm previously described.²⁵ Participants without at least one PRO-CTCAE assessment were excluded from this analysis.

Other Measures

Randomization was stratified by recruitment site (Kaiser Permanente Northern California vs. Dana-Farber Cancer Institute vs. Penn State Cancer Institute), sex (male vs. female), cancer stage (II vs. III), chemotherapy regimen (FOLFOX vs. CAPEOX vs. 5-FU/LV vs. capecitabine monotherapy), and chemotherapy duration (3 vs. 6 months). Race and ethnicity were self-reported using the National Institutes of Health categories. At baseline, study staff measured height and weight following standardized procedures or recorded from electronic medical records to calculate body mass index (BMI).

Statistical Analysis

Only participants receiving oxaliplatin as part of their chemotherapy regimen (FOLFOX, 5-FU/leucovorin and oxaliplatin; or CAPOX, capecitabine and oxaliplatin) were included in this analysis. Participant characteristics at baseline are reported as mean ± standard deviation for continuous variables or as counts with percentages for categorical variables. AHEI-2010 scores were used as continuous variables in all analyses.

CIPN was analyzed as a composite endpoint of moderate or severe (moderate-severe), because both severities are clinically relevant for chemotherapy dose reductions.²⁶ Severe only CIPN was investigated in exploratory analysis. The association between baseline diet quality and the hazard of incident moderate-severe or severe CIPN was modeled using the Cox proportional hazards model. The assumption of proportional hazards was examined by visual inspection of graphical log-log plots and tested statistically in a generalized linear model of the scaled Schoenfeld residuals on time. The unit of time for the Cox proportional hazards model was time in weeks to moderate-severe CIPN. To assess risk for any given AHEI-2010 score, a reference point for each spline was chosen as the 10^th percentile score for the AHEI-2010 (52.6). A negative outcome control analysis among the subset of participants not treated with oxaliplatin was conducted to detect unmeasured confounding of the association between the AHEI-2010 score and the time until moderate-severe CIPN (e.g., participants not treated with oxaliplatin should not develop or have a worsening of CIPN and if such an association was detected, it would suggest unmeasured confounding).²⁷ The association with the time until of moderate-severe or severe CIPN with average servings per day of individual food or beverage components of the AHEI-2010 was explored using the Cox proportional hazards model and reported as hazard ratios (HR) with 95% confidence intervals (95% CI). To qualitatively assess the food and beverage component patterns between a higher and lower diet quality index score, participants were separated into quintiles based on the overall AHEI-2010 score, and the components were mapped using radar plots. The mean component score for each quintile was calculated, and the first (lowest diet quality) and fifth (highest diet quality) quintiles were included to contrast component scores between these quintiles. Covariates used in all models included sex, race (Other vs. White), age (< 60 years vs. ≥ 60 years), kcal/day (continuous),²⁸ randomization site, intervention (resistance training vs. control), a categorical variable representing whether participants had enrolled before chemotherapy cycle 1 or cycle 2, baseline body mass index (continuous), and chemotherapy regimen duration (3-months vs. 6-months). All analyses were two-sided, and P<0.05 was considered statistically significant. Statistical analyses were completed using SAS Windows version 9.4 (SAS Institute; Cary, NC) and R version 4.1.3 (https://www.R-project.org/).

RESULTS

A total of 181 participants were randomized between February 2018 and September 2021. Of these participants, 165 received oxaliplatin-based chemotherapy, and 132 had PRO-CTCAE and baseline dietary data available (Figure S1). Compared to the randomized sample, participants who did not receive oxaliplatin were older (P=0.008), more likely to have stage II disease (P<0.001), and be prescribed 6 months of chemotherapy (P=0.003). Those missing the PRO-CTCAE were older (P=0.05), prescribed CAPOX (P=0.01), and differed by randomization site (P<0.001). Individuals missing dietary data only differed from the total randomized sample by randomization site (P=0.004) (Table S2).

The mean (SD) age of the participants included in this analysis was 53.9 (12.8) years; 67 (50.8%) were female; 83 (62.9%) were treated with FOLFOX; 87 (62.9%) were treated for 6 months; and the mean (SD) BMI was 27.2 (5.3) kg/m² (Table 1). A total of 74 (56.1%) reported moderate-severe CIPN. The mean (IQR) time to develop moderate-severe CIPN was 11.0 (IQR: 4.0-18.0) weeks. A total of 23 (17.4%) experienced severe CIPN, with an average of 11.7 (IQR: 5.9-19.9) weeks to develop severe CIPN. Twelve participants (16%) developed only severe CIPN.

Table 1:

Demographic characteristics of study participants

Variable	Mean (SD) or n (%)
Age (continuous)	53.9 (12.8)
Sex, n (%)
Male	65 (49.2)
Female	67 (50.8)
Race, n (%)
African American or Other	41 (31.1)
White	91 (68.9)
Site, n (%)
DFCI	37 (28.0)
Kaiser	89 (67.4)
Penn State	6 (4.6)
Stage, n (%)
Stage II	11 (8.3)
Stage III	121 (91.7)
Regimen, n (%)
CAPOX	49 (37.1)
FOLFOX	83 (62.9)
Treatment duration, n (%)
3 months	45 (34.1)
6 months	87 (65.9)
Randomization time
Before Cycle 1	67 (50.8)
Before Cycle 2	65 (49.2)
Intervention, n (%)
Control	66 (50.0)
Resistance Training	66 (50.0)
BMI	27.2 (5.3)
AHEI-2010 (continuous)	64.7 (9.2)
Calories (continuous)	1698.0 (678.8)
CIPN
No CIPN	58 (43.9)
Moderate-severe	74 (56.1)
Severe	23 (17.4)
Time to develop moderate-severe CIPN (weeks, mean (IQR))	11.0 (4.0-18.0)
Time to develop severe CIPN (weeks, mean (IQR))	11.7 (5.9-19.9)

Abbreviations: standard deviation (SD); Interquartile range (IQR); Dana-Farber Cancer Institute (DFCI); Kaiser Permanente Northern California (Kaiser); Penn State Cancer Institute (Penn State); capecitabine and oxaliplatin (CAPOX); 5-FU/leucovorin and oxaliplatin (FOLFOX); chemotherapy-induced peripheral neuropathy (CIPN); body mass index (BMI); Alternative Healthy Eating Index (AHEI-2010).

AHEI-2010 and CIPN

The mean (SD) diet quality score for AHEI-2010 was 64.7 (9.2) and ranged from 42.1 to 86.9. Higher dietary quality was associated with a significantly lower risk of moderate-severe CIPN [HR: 0.96, 95% CI: 0.93, 0.99], with a 4% lower risk per point increase in AHEI-2010 (Figure 1A). Individuals with a median dietary quality score (65.3) had a 51% lower risk of moderate-severe CIPN [HR: 0.49 (0.34, 0.60)] compared to the 10^th percentile AHEI-2010 score (52.6). In the negative outcome control analysis, AHEI-2010 was not associated with the risk of moderate-severe CIPN [HR: 0.97 (0.85, 1.10)]. Consumption of red and processed meat [HR: 1.78 (1.07, 2.83)] and sugar-sweetened beverages [HR: 1.33 (1.10, 1.59)] were associated with a significantly higher risk of moderate-severe CIPN (Table 2).

Figure 1. Spline of Risk of Moderate and/or Severe CIPN by Diet Quality.

Cox proportional hazards model of association between AHEI-2010 score with moderate-severe CIPN (A) and severe CIPN (B). Dashed vertical lines represent the 10^th percentile AHEI-2010 score (52.6) as the reference point. Abbreviations: chemotherapy-induced peripheral neuropathy (CIPN); Alternative Healthy Eating Index-2010 (AHEI-2010).

Table 2:

Association of AHEI-2010 components with hazard rate of moderate-severe CIPN

Moderate-severe CIPN
AHEI-2010	HR (95% CI)
Vegetables (serv/day)	0.82 (0.54, 1.21)
Fruit (serv/day)	0.80 (0.62, 1.00)
Whole grain (g/day)	0.98 (0.95, 1.01)
Polyunsaturated fat (% energy)	1.01 (0.88, 1.16)
Sodium (mg/day)	1.00 (1.00, 1.00)
Sugar sweetened beverages (serv/day)	1.33 (1.10, 1.59)
Nuts and legumes (serv/day)	0.65 (0.40, 1.01)
Red and processed meat (serv/day)	1.78 (1.07, 2.83)
Trans fat (% energy)	1.74 (0.65, 4.31)
Omega fatty acids (mg/day)	1.00 (1.00, 1.00)
Alcohol (drinks/day)	0.96 (0.71, 1.25)

Abbreviations: Alternative Healthy Eating Index (AHEI-2010); chemotherapy-induced peripheral neuropathy (CIPN); hazard ratio (HR); confidence interval (CI); servings (serv); grams (g); milligrams (mg). Adjusted for: sex, race, age, kcal/day randomization site, intervention, enrollment before chemotherapy cycle 1 or cycle 2, baseline BMI, and chemotherapy regimen duration

In exploratory analyses, higher diet quality was significantly associated with a lower risk of severe CIPN [HR: 0.91 (0.85, 0.98)] (Figure 1B). Participants with a median AHEI-2010 diet quality score had a 65% lower risk of severe CIPN [HR: 0.35 (0.21, 0.60)] compared to the 10^th percentile. Sugar-sweetened beverages were also associated with a higher risk of severe CIPN [HR: 1.57 (1.14, 2.18)], whereas vegetables were associated with a lower risk of severe CIPN [HR: 0.29 (0.09, 0.73)] (Table S3).

When examining the component scores between the highest and lowest quintiles of AHEI-2010 score (i.e., highest diet quality versus lowest diet quality), both quintiles had similar scores for omega fatty acids, trans fat, nuts and legumes, and whole grain. The highest diet quality quintile received higher scores for fruit, vegetables, and alcohol. For negatively scored components (i.e. lower consumption equals higher scores), the highest diet quality quintile had higher scores for sodium, red/processed meat, and sugar-sweetened beverages. (Figure 2).

Figure 2. AHEI-2010 Components by Lowest and Highest Quintile.

Radar plot showing the average score of the components of the AHEI-2010 index for the lowest (first) and highest (fifth) quintile AHEI-2010 score, representing the lowest diet quality score and the highest, respectively. Higher scores represent more favorable consumption of components. Higher scores for negatively scored components (red/processed meat, sugar-sweetened beverages, trans fat, and sodium) represent lower consumption. Abbreviations: Alternative Healthy Eating Index-2010 (AHEI-2010).

DISCUSSION

In a cohort of 132 colon cancer patients receiving oxaliplatin-based chemotherapy, higher dietary quality was associated with a lower risk of developing moderate-severe and severe CIPN. Sugar-sweetened beverages and red/processed meat were associated with an increased risk of moderate-severe CIPN. Vegetables were associated with a lower risk of severe CIPN. If these associations are causal, this analysis suggests that a higher-quality diet may help prevent or delay the incident CIPN during oxaliplatin-based chemotherapy.

CIPN is a dose-limiting toxicity of oxaliplatin. Incident CIPN requires oxaliplatin dose delays, dose reductions, or cessation of drug administration,²⁹ which may compromise disease-free and overall survival.^8,9,30,31 Patients who develop severe CIPN are more likely to experience chronic neuropathy after treatment is completed.⁵ Pain, cold sensitivity, and tingling caused by CIPN reduce quality of life and physical function.³² Most patients will experience CIPN after the first treatment of oxaliplatin;⁵ therefore, delaying or reducing the risk of incident CIPN may improve these outcomes.

While guidance for nutrition interventions during cancer treatment is limited,³³ nutrition is a common concern for patients and providers.^10–13 Patients whose physicians provide recommendations regarding diet and other lifestyle factors are more likely to improve these behaviors.³⁴ Diet may be a method by which to delay CIPN development. The results of this analysis support the importance of maintaining a healthy dietary pattern during cancer treatment. Encouraging patients to reduce their consumption of sugar-sweetened beverages and red/processed meat and increase vegetable intake may be a practical means to improve overall dietary quality.

While the exact mechanisms of CIPN development are incompletely elucidated, hypothesized pathways include oxidative stress and inflammation,^35,36 mitochondrial dysfunction,³⁷ immune function,³⁸ and ion channel function.^39,40 Certain foods may act on these pathways in conjunction with oxaliplatin treatment to contribute to the development of CIPN. In this analysis, sugar-sweetened beverages were associated with an increased risk of CIPN. Excess sugar-sweetened beverage consumption contributes to chronically elevated blood glucose and increased caloric intake, promoting poor glycemic control and inflammation.^41–43 Hyperglycemia and type 2 diabetes cause peripheral neuropathy through microangiopathy and damaging nerve cells via oxidative stress.⁴⁴ This is relevant to chemotherapy, where many patients receive corticosteroids⁴⁵ that impact the ability to control blood glucose.⁴⁶

Red/processed meat, which is calorically dense and high in saturated fats, was also associated with an increased risk of CIPN. When consumed in excess, these foods contribute to positive energy balance and risk of cardiovascular disease and diabetes.⁴⁷ In preclinical models of diabetic peripheral neuropathy, hyperlipidemia dysregulates mitochondrial function and neural lipid profiles.^48–50 Together, these dietary mechanisms may compound with oxaliplatin to help contribute to CIPN. Additional studies on the mechanisms by which diet impacts CIPN are needed.

This study has several limitations to acknowledge. This study used a solitary assessment of dietary intake at the start of chemotherapy, and longitudinal changes in diet were not captured. Future studies investigating longitudinal diet quality during chemotherapy are necessary. Dietary intake was assessed using an FFQ, which has the known limitation of participant recall. Diabetes status and corticosteroid use of participants was not collected. Since diabetes is associated with the severity of CIPN,⁵¹ including this confounder may have attenuated the strength of the identified associations. Diet quality was assessed using the AHEI-2010. However, we focused on the AHEI-2010 based on its specificity to chronic disease risk over other scores such as the Healthy Eating Index (HEI).^23,24 This participant cohort is younger than the average age of colon cancer patients.⁵² Our negative control analysis was based on a small subset of patients who did not receive oxaliplatin, and residual confounding may not be completely ruled out; however, residual confounding is a potential in all observational studies. In our models investigating individual AHEI components, we could not mutually adjust for all score components due to low statistical power. Lastly, this analysis was not prespecified in the protocol’s statistical analysis plan; therefore, these results should be considered hypothesis generating.

This study also has several strengths. CIPN was patient-reported and measured repeatedly during chemotherapy. This allowed us to assess the time until moderate-severe CIPN occurred, rather than a cross-sectional, retrospective rating at the end of chemotherapy. Measuring dietary quality better reflects the habitual consumption of an individual in terms of food combinations, quantities, and variety.¹⁴ The FORCE trial was conducted at three sites across the United States, which helps generalize the study findings.

The results from this analysis suggest that higher baseline dietary quality is associated with a lower risk of developing moderate and/or severe CIPN. Consumption of sugar-sweetened beverages and red/processed meat was associated with an increased risk of CIPN. This study supports an emphasis on maintaining or improving dietary quality as much as possible during cancer treatment. Future studies are needed to replicate these results. The findings from this analysis may be particularly informative for designing future randomized trials of nutrition and diet quality to prevent, delay, or reduce CIPN.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author on reasonable request.