The Effect of Serum 25(OH)D3 Level on Breast Cancer-Related Lymphedema

Abstract

Background:

The aim of this study was to evaluate the effect of serum 25-hydroxyvitamin D3 [25(OH)D3] levels on the presence and severity of lymphedema, and on the levels of pain, disability, and function in patients with breast cancer-related lymphedema (BCRL).

Methods and Results:

This controlled study included 71 patients diagnosed with breast carcinoma. Participants were divided into two groups. The BCRL group included 37 breast cancer patients with lymphedema and the control group included 34 breast carcinoma patients without lymphedema. Demographic information, dominant extremity, affected breast, duration of malignancy, and serum 25(OH)D3 levels were recorded for all patients. The 25(OH)D3 levels were then compared between groups. The correlations between serum 25(OH)D3 levels and the visual analog scale (VAS) and Quick Disabilities of the Arm, Shoulder, and Hand Questionnaire (Q-DASH) scales and the volumetric and diametric differences between the upper extremities were analyzed in the BCRL group. Serum 25(OH)D3 levels did not show statistically significant differences between groups (p > 0.05). There was no correlation in the BCRL group between 25(OH)D3 levels and the VAS and Q-DASH scores or the diametric and volumetric differences of extremities (r ≤ 0.3; p > 0.05).

Conclusions:

Serum 25(OH)D3 levels do not appear to affect the presence or severity of lymphedema, pain, disability, or physical function in BCRL patients. In routine clinical practice, evaluation of this vitamin level does not appear to be necessary for lymphedema in BCRL patients.

Introduction

Breast cancer is the second most prevalent cancer worldwide and the most common cancer among the female population.¹ Breast cancer-related lymphedema (BCRL) is a common consequence of breast cancer treatment.² It results from lymphatic insufficiency leading to a progressive inflammatory process that ultimately manifests as discomfort and recurrent infections.^3,4 Patients with BCRL in the ipsilateral upper extremity suffer from experiencing swelling, heaviness, pain, numbness, stiffness, and impairment of limb mobility, strength, and dexterity. BCRL can lead to physical changes and limitations on range of motion, daily living activity, function, personal care, and recreational and social relationships. BCRL may also cause work and financial problems.^2–11

25-Hydroxyvitamin D3 [25(OH)D3] plays a role in physical performance and muscle and bone functions.^12,13 Several trials have shown an inverse association between serum 25(OH)D3 levels and incidence and mortality rates of breast carcinoma.^14,15 Vitamin D supplementation may also be effective in breast cancer prevention.¹⁶ However, to the best of our knowledge, there have been no studies evaluating the relationship between lymphedema in breast cancer patients and 25(OH)D3 in the literature until recently.

The primary aim of this study was to compare serum 25(OH)D3 levels among breast carcinoma patients with and without BCRL. The secondary aim was to evaluate whether or not there was a correlation between the serum 25(OH)D3 level and clinical evaluation, pain, disability, and function in patients with BCRL.

Materials and Methods

This controlled study was approved by the Baskent University Institutional Review Board and Ethics Committee (project no: KA16/14) and supported by the Baskent University Research Fund. Written informed consent was obtained from all participants.

Power analysis during the biostatistical preliminary assessment indicated a study population of 66 patients (33 patients for each group) with 95% confidence level and 80% power.¹⁷

The study population was categorized into two groups. Inclusion criterion of the first group (BCRL group) was diagnosis of unilateral upper extremity BCRL (n = 37; mean age: 53.13 ± 10.5 years). The second group consisted of patients diagnosed with unilateral breast cancer without lymphedema (n = 34; mean age: 55.42 ± 12.13 years) and served as the control group (n = 34). All patients were treated surgically, including axillary lymph node dissection and received chemotherapy and radiotherapy.

Exclusion criteria were bilateral breast carcinoma, bilateral BCRL, vitamin D replacement treatment, and history of metabolic bone disease and kidney or liver disease that affects vitamin D metabolism.

Age, body mass index (BMI) (body weight [kg]/height² [m²]), education level, work status, dominant extremity, affected breast, duration of malignancy diagnosis, and serum 25(OH)D3 levels were recorded for both groups. Serum 25(OH)D3 levels <20 ng/mL were stated as vitamin D deficiency, whereas 25(OH)D3 serum levels between 21 and 29 ng/mL were defined as vitamin D insufficiency.^15,18

The visual analog scale (VAS) score, Quick Disabilities of the Arm, Shoulder, and Hand Questionnaire (Q-DASH) score, and volumetric and diametric differences between the affected and unaffected extremities were recorded. Patients in the second group did not describe any pain, weakness, or limitation of their upper extremity function secondary to breast carcinoma. For this reason, VAS and Q-DASH were evaluated only in patients in the BCRL group.

Lymphedema evaluation

Measurements of differences in limb volume and size were used for the evaluation of BCRL. Diagnosis criterion for BCRL was identified as a difference of or >200 mL in upper limb volume or a circumferential difference of ≥2 cm at any of these points between the affected and nonaffected upper limbs.^19,20 Patients meeting one or both of these criteria were defined as having lymphedema.

Before measurements were taken, patients were asked to remove all jewelry and watches from their hands and wrists. Volumetric measurement differences between the upper extremities were made using the water displacement method. A larger water container with an overflow pipe that drains into another smaller container was filled with warm water up to a mark at the lower border of the overflow pipe. Each arm was placed in the container in turn and the volume of water that was displaced was recorded. The circumferential measurement differences method was performed using a narrow flexible nonstretch tape measure. Measurements were performed at the level of the metacarpophalangeal joint, wrist, 10 cm distal to the lateral epicondyle, 10 cm proximal to the lateral epicondyle, and 20 cm proximal to the lateral epicondyle.

Lymphedema stage of all BCRL patients was evaluated. Stage 1 presents with pitting edema and is reversible. Stage 2 occurs as the edema progresses and becomes more intense, nonpitting, and irreversible. Stage 3 is characterized by advanced lymphedema. Cartilaginous hardening is observed in conjunction with papillomatous outgrowths and hyperkeratosis of the skin in this stage.²⁰

Visual analog scale

The severity of pain was assessed using the VAS scale, which evaluates subjective pain intensity. The VAS is a pain scale visualized as a 10 cm straight line with the left side defined as having absolutely no pain and the right as having maximum pain. Pain levels were assessed by asking subjects to mark their pain level on the VAS.^12,21

The Quick Disabilities of the Arm, Shoulder, and Hand Questionnaire

This scale is a shortened version of the DASH scale and measures physical function and symptoms in patients with musculoskeletal disorders of the upper limb. The questionnaire consists of a disability/symptom scale (11 items) and two optional scales: work (4 items) and sports/performing arts (4 items). In the disability/symptom scale, each item asks about the severity of pain, activity-related pain, tingling, weakness and stiffness, difficulty in performing physical activities because of the upper extremity problem/s, and the effect of the upper extremity problem/s on social activities, work, and sleep. Two optional modules measure the ability to work and the ability to perform sports and/or play musical instruments. Answers are given based on a one-to-five scale and each question is scored between 1 and 5. The scores of three subscales of Q-DASH, the disability/symptom, work, and sports/performing arts scales, ranged between 0 (no disability) and 100 (most severe disability). The Turkish translation of the Q-DASH was performed by Koldas Dogan et al.²²

Statistical analysis

Statistical analysis was performed using the statistical package SPSS (Version 17.0; SPSS, Inc., Chicago, IL). Normal continuous variables were described as the mean ± standard deviation (p > 0.05 in Kolmogorov–Smirnov test or Shapira–Wilk [n < 30]) and not normal variables were described as the median. Comparisons between groups were applied using the one-way Student's t-test for normally distributed data and the Mann Whitney U test for data that were not normally distributed.

Correlations between outcome scores and 25(OH)D3 were tested using the Spearman's correlation test. Correlation coefficients were interpreted as either excellent relationship r ≥ 0.91, good 0.90 ≥ r ≥ 0.71, fair 0.70 ≥ r ≥ 0.51, weak 0.50 ≥ r ≥ 0.31, little, or none r ≤ 0.3. A p-value of 0.05 was taken as the level of significance.²³

Results

The BCRL and control groups included 37 and 34 female patients, respectively.

In the BCRL group, 16 patients were evaluated in lymphedema Stage 1, 14 patients in Stage 2, and 7 patients in Stage 3.

Clinical characteristics of the study population did not show statistically significant differences between groups (p > 0.05), with the exception of BMI that was significantly higher in the BCRL group than in the control group (p = 0.029). Clinical characteristics of each group are summarized in Table 1.

Table 1.

Clinical Characteristics of the Study Population

Characteristics	BCRL group (n = 37)	Control group (n = 34)	p
Age (years), mean ± SD	53.13 ± 10.5	55.42 ± 12.13	0.354
Body mass index (kg/m²), mean ± SD	31.64.6 ± 5.19	29.03 ± 3.84	0.029
Duration of malignancy (months), mean ± SD	43.09 ± 34.08	37.68 ± 33.92	0.687
Dominant extremity (right/left), n	28/9	22/12	0.436
Affected breast (right/left), n	20/17	22/12	0.470
Work status
Housewife/active working/retired, n	22/8/7	24/5/5	0.608
Education level
No school/elementary school/middle school/high school/college/master, n	6/7/11/4/5/4	2/3/13/6/8/2	0.351

Statistically significant values are indicated in bold.

BCRL, breast cancer-related lymphedema; SD, standard deviation.

Serum 25(OH)D3 level was similar between groups (p = 0.468). Serum 25(OH)D3 status is given in Table 2.

Table 2.

Serum 25(OH)D3 Status of the Study Population

Characteristics	BCRL group (n = 37)	Control group (n = 34)
Serum level of 25(OH)D3 (ng/mL)^a	10.20 (4–35)	12.7 (4–46)
Vitamin D deficiency (<20 ng/mL), n	27	27
Vitamin D insufficiency (21–29 ng/mL), n	8	6
Vitamin D sufficiency (>30 ng/mL), n	2	1

Median (minimum–maximum).

25(OH)D3, 25-hydroxyvitamin D3.

Correlations between outcome measurements and serum 25(OH)D3 levels in the BCRL group were analyzed. For correlation analysis, the outcome variables of each patient in the BCRL group were evaluated. No significant correlation of outcome measurements with serum level of 25(OH)D3 was found (r ≤ 0.3; p > 0.05). Outcome measurements and correlation analysis results are given in Table 3.

Table 3.

Correlation Analysis Results of 25(OH)D3 Levels Between Outcome Measurements of the Breast Cancer-Related Lymphedema Population (n = 37)

Characteristics	Value^a	r	p
Duration of BCRL (months)	6 (1–120)	0.001	0.679
Body mass index (kg/m²)	31.63 (21.36–43.75)	−0.073	0.587
Visual analog scale	3 (0–8)	−0.03	0.45
Q-DASH	15 (0–68)	−0.052	0.699
Volumetric measurement difference between upper extremities (mL)	412 (225–1840)	−0.033	0.803
Circumferential measurement difference between upper extremities (cm)
Metacarpophalangeal joint	0.5 (0–5.5)	−0.064	0.632
Wrist	0 (1–5.5)	−0.098	0.460
10 cm distal to the lateral epicondyle	2.25 (0–10)	−0.027	0.837
10 cm proximal to the lateral epicondyle	2.5 (1–12)	−0.055	0.678
20 cm proximal to the lateral epicondyle	1.75 (0–8)	−0.156	0.237

Median (minimum–maximum).

Q-DASH, Quick Disabilities of the Arm, Shoulder, and Hand Questionnaire.

Discussion

To our knowledge, this is the first study evaluating the relationship between BCRL and serum 25(OH)D3 levels. For this purpose, we compared serum 25(OH)D3 levels of BCRL and control patients and found that levels did not differ among groups. For this reason, we believe that this vitamin may not have an effect on the presence of BCRL. Lymphedema results in chronic inflammation, fibrosis, immunosuppression, and increased tendency for infections.²⁴ Some studies noted that vitamin D is related with immune response. Insufficient supply of vitamin D may lead to the dysregulation of the human immune response.¹³ Our hypothesis was that vitamin D levels can affect BCRL due to its effect on the immune response. However, as vitamin D levels were similar between groups, we were unable to confirm this hypothesis. In addition, there was no relationship between serum 25(OH)D3 levels and VAS scores or differences in upper limb size and volume. Based on this, we believe that serum 25(OH)D3 levels do not affect lymphedema and pain in these patients.

Vitamin D has a role in bone health and function and has positive effects on muscle physiology, function, and motor performance. Several studies have demonstrated that low serum 25(OH)D3 levels correlate with poor physical performance and decreased physical activity.¹⁰ However, Q-DASH scores of our BCRL population were not correlated with serum level of 25(OH)D3 level. For this reason we thought that vitamin D may not affect on disability and function in BCRL patients.

Estébanez et al.²⁵ researched vitamin D exposure and breast carcinoma risk in a meta-analysis and concluded that high serum levels of 25(OH)D3 have a protective effect on breast cancer risk in premenopausal women. In the literature, serum 25(OH)D3 levels were shown to be positively associated with low risk of breast cancer, less aggressive disease, and lower mortality rates.^{15,16,26–28} Streb et al.²⁹ compared 25(OH)D3 levels of breast carcinoma patients with 28 healthy subjects in the control group. They found that serum 25(OH)D3 levels were lower in patients with breast cancer than in the healthy subjects and suggested that although a significant decrease in 25(OH)D3 level was observed, the supplementation of vitamin D should be considered during the course of therapy. Similarly, Tommie et al.³⁰ suggested that the women should be routinely screened for 25(OH)D3 deficiency. According to this opinion, vitamin D can be supplemented in patients with breast cancer due to its effects on optimal bone and muscle functions, proper immune response, reduced inflammation, and improved quality of life.^15,31 Conversely, in this study, vitamin D was not found to have an effect on BCRL.

BMI was categorized as underweight (BMI 15–19.9), normal weight (BMI 20–24.9), overweight (BMI 25.0–29.9), and obese (BMI ≥30).³² Fu et al. reported that higher BMI can increase the risk of lymphedema.¹⁹ Vitamin D deficiency is correlated with obesity.^27,33 In this study, BMI was higher in the BCRL group than in the control group. Based on this, higher BMI score is thought to be related with BCRL.

The first limitation of this study was that most patients in our study group had low-grade BCRL. For this reason and because of the small sample size, we were unable to analyze the relationship between BCRL stage and 25(OH)D3 levels. Further studies with a larger population that include patients with high-grade BCRL may lead to more specific and significant results. The determination of lymphedema using volumetric and diametric differences could affect our results. Future studies using more objective assessment methods such as perometry or lymphoscintigraphy would eliminate this disadvantage and strengthen further analysis.

In conclusion, serum 25(OH)D3 level does not appear to be related to the presence or severity of BCRL. Vitamin D level was not shown to affect pain, disability, physical function, or extremity size, or volume in BCRL patients. In routine clinical practice, evaluation of this vitamin level does not appear to be necessary in patients with BCRL. Studies on this issue can be performed with larger sample sizes and high-grade BCRL to provide further perspective on this subject.

Footnotes

Acknowledgment

The authors thank Cagla Sarıturk for performing biostatistical analysis.

Ethical Approval

All procedures involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Author Disclosure Statement

No competing financial interests exist.

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