Effects of dietary habits and catheterization type on breast cancer-related lymphedema: a retrospective cohort study

doi:10.21203/rs.3.rs-1747158/v1

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Effects of dietary habits and catheterization type on breast cancer-related lymphedema: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-1747158/v1

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Background Understanding the factors that contribute to variability in breast cancer-related lymphedema (BCRL) is an important first step in developing targeted interventions to improve quality of life in breast cancer patients. Although previous research studies have has identified many risk factors for BCRL, dietary habits and catheterization type have rarely been studied until the present.This study aims to explore the effects of dietary habits and catheterization type on BCRL.

Methods This study included 1,476 breast cancer patients after surgery between January 1, 2010 and September 1, 2020. Lymphedema was assessed with a validated self-reported questionnaire. All research data was obtained by medical records and follow-up database. Survival analysis was conducted to explore the effects of dietary habits and catheterization type on BCRL.

Results The result showed an increased risk for BCRL among breast cancer patients who followed a high-fat diet pre-hospitalization (hazard ratio [HR] =2.473; P<0.001), indwelling totally implantable venous access ports (TIVAPs) compared with indwelling needle (HR=0.558; P=0.017) and indwelling TIVAPs, compared with anindwelling peripherally inserted central catheter (PICC) (HR=0.691; P=0.086).

Conclusion High-fat diet pre-hospitalization was an independent risk factor for lymphedema. The TIVAPs did not exert a protective effect on lymphedema compared with the PICC and indwelling needle. This study finding offers new insights to develop targeted interventions to decrease the incidence of lymphedema.

Lymphedema

Breast cancer

Dietary habits

Catheterization type

Although the incidence of breast cancer is high, with progress in diagnosis and therapy, the research and development of new drugs and the continuous development of standardized treatment, the five-year survival rate of patients with breast cancer has improved significantly [1, 2]. However, lymphedema caused by breast cancer treatment is very prominent, with an incidence of 8.4%-54.0% [3]. The symptoms of lymphedeman includes heaviness, discomfort, elephantiasic crus, reduced range of motion, as well as depression, anxiety and body image changes[4, 5]. These effects last for a long time after treatment and may be permanent, adversely affecting patient quality of life [6–8]. Understanding the factors that contribute to variability in BCRL is the key step in developing targeted interventions to reduce the incidence of BCRL.

Previous research has identified risk factors for breast BCRL, including increased obesity, chemotherapy treatment, radiation therapy, surgery way and the number of lymph nodes removed, etc[3, 9, 10]. However, researchers have spent little time studying the effects of diet and catheterization type on lymphedema occurrence [3].

The latest systematic review and meta-analysis of lymphedema has found that hypertension, diabetes and obesity are risk factors for lymphedema [3, 9, 11–13]. In the meantime, a high-fat diet is a common risk factor for hypertension, diabetes and obesity. Hypertension, diabetes and obesity are largely preventable through diet modifications [14–17]. Thus, we propose that a high-fat diet may also exert a negative influence on BCRL, and lymphedema might be preventable through diet modifications. At present, few studies have focused on the relationship between dietary habits and BCRL. Due to medical interventions in hospital, patient dietary habits may be different before and after hospitalization. Therefore, patients’ diets, pre- and post-hospitalization should be studied separately. This study will separately examine the effects of pre- and post-hospitalization dietary habits on BCRL.

The primary functions of lymphatic system is to collect the fluid leaking at the capillary level, remove water and protein, and eventually return to venous circulation at shoulder level via the subclavian vein[18]. Therefore, we guess a peripherally inserted central catheter (PICC) that passes through the subclavian vein may cause some damage to the subclavian vein and affect the reflux of lymph, resulting in the occurrence of lymphedema. At present, our department gradually indwelled TIVAPs inserted through the jugular vein and placed in the chest instead of the arm. In other words, the TIVAPs do not pass through the subclavian vein and will not damage the subclavian vein. So we hypothesized that the TIVAPs exert a certain protective effect on BCRL, compared with the PICC.

Thus, the aim of this study is to explore the effects of dietary habits and catheterization type on BCRL. Based on our review, we hypothesized that: (i) a high-fat diet would be a risk factor for BCRL; (ii) the TIVAPs would exert a protective effect on lymphedema compared with the PICC.

Design, setting and population

A total of 1,476 post-surgery breast cancer patients in the breast surgery ward of a single university hospital in Hunan Province were included in our study between January 1, 2010 and September 1, 2020.

The number of breast cancer patients in the hospital during the study period determined the sample size. Inclusion criteria were as follows: (1) patients diagnosed with breast cancer by pathological examination; (2) no adjacent organ invasion and distant metastasis organ before operation; (3) patients who received surgery-related treatment of breast cancer in our department; (4) patients voluntarily participated in the study and signed the informed consent form.

The exclusion criteria were as follows: (1) patients diagnosed with breast cancer but breast cancer was not the primary tumor; (2) patients also diagnosed with other cancer; (3) patients who died during the perioperative period; (4) patients who did not receive adjuvant therapy in our department; (5) patients with severe or uncontrollable mental illness.

Instruments for lymphedema measurement

Differences in limb volume or circumference have widely been used to assess the presence and degree of lymphedema, however, it is not feasible to the large cohort for the great cumulative cost of repeated measurement at each follow-up over time. Thus, in our study, we used a widely questionnaire to assess lymphedema presence in which lymphedema was assessed by patient’s reported difference in the size of her hands, lower arms and upper arms [19]. This questionnaire has been commonly used in the restrospective cohort study [3, 20].

Specifically, to reduce information bias, we trained professional case managers to follow up with patients and build up the cohort. During the first telephone interview, the case manager asked patients: “Between the date of breast cancer surgery and the interview date, on average, whether your right and left hands, lower arms or upper arms seemed to deffer in size.” Subsequent telephone interviews covered the time period extending back to the previous interview. During adjuvant therapy, the case managers followed up with patients once a month. Otherwise, the case managers followed up with patients once every three months in the two years after surgery, once every six months from two to five years after surgery, and once each year after five years.

Statistical analysis

Descriptive analysis was used to describe cohort demographics, disease and treatment characteristics. The Kaplan-Meier method was conducted to calculate the cumulative incidence of BCRL and identify the possible differences in the curves for the different stratums of risk factors. Univariate Cox regression was conducted to estimate the risk factors for BCRL roughly. And variables with P < 0.05 in the Univariate Cox regression analysis were included in the Multivariate Cox regression analysis to further explore the effects of dietary habits and catheterization type on lymphedema. Generally, for Multivariate Cox regression, the number of positive events (122) should be greater than or equal to 10 times the number of independent variables (7) included in the model[21]. Thus, our study’s sample size is large enough to answer the research question meaningfully.

A total of 1,476 patients was included in this study, of whom 122 developed lymphedema, with an incidence of 14.2% at five years follow-up and 15.8% at 10 years follow-up. Lymphedema probability is presented in Fig. 1. And censored data included: (1) A total of 86 patients lost to follow-up (‘lost to follow-up’ in this case is defined as patients who could not be reached by telephone (they were called three times, with no response) ; (2) A total of 95 patients who died for any reason and did not develop lymphedema before death; (3) A total of 1,173 patients who did not develop lymphedema, but the time limit set by the study had passed.

[Insert Fig. 1 here]

Table 1 presented patient demographic characteristics, disease characteristics and treatment characteristics. The majority of patients were married (97.9%) and had a junior middle school education (55.7%). Most patients were 45–60 years old (58.1%) and the body mass index(BMI) of most patients was normal (56.3%), with only 8.1% of patients who followed a high-fat diet pre-hospitalization. The tumor size of most patients was 2-5cm (54.1%). Most patient histopathological staging was stage Ⅱ (48.7%) without lymph node metastasis (58.5%). Only 20.6% of patients had a sentinel-node biopsy. Most patients had chemotherapy (81.8%), while only 15.5% of patients had radiotherapy. Most patients had indwelled TIVAPs (48.1%).

Table 1

Lymphedema risk in accordance with demographic characteristics, disease characteristics and treatment characteristics
	Frequency N(%)	Missing N(%)	P-value	HR ( 95.0% CI )
Demographic Characteristics
Education		0(0)	0.859	0.980(0.788–1.220)
Primary school or below	312(21.1)
Junior middle school	822(55.7)
Senior high school	238(16.1)
Bachelor or master	104(7.0)
Marital status		0(0)	0.110
Unmarried	12(0.8)		1
Married	1445(97.9)		0.044	0.309(0.098–0.971)
Divorced or widowed	19(1.3)		0.441	0.495(0.083–2.963)
Preoperative eating habits		0(0)	0.000^***	2.515(1.585–3.991)
Low-fat diet	1357(91.9)
Hight-fat diet	119(8.1)
Postoperative eating habits		0(0)	0.578	0.049(0-1972.048)
Low-fat diet	1471(99.7)
Hight-fat diet	5(0.3)
Hypertension		0(0)	0.737	1.094(0.647–1.851)
No	1303(88.3)
Yes	173(11.7)
Diabetes		0(0)	0.184	0.460(0.146–1.446)
No	1405(95.2)
Yes	71(4.8)
Affected limb trauma		0(0)	0.541	0.049(0-765.698)
No	1465(99.3)
Yes	11(0.7)
Age		0(0)	0.217
< 45	265(18.0)		0.467	1.253(0.682–2.302)
45–60	858(58.1)		0.087	1.499(0.943–2.384)
≥ 60	353(23.9)		1
BMI		101(6.8)	0.083
< 18.5	54(3.9)		0.579	0.726(0.234–2.252)
18.5–23.9	774(56.3)		0.169	0.645(0.345–1.205)
24-27.9	436(31.7)		0.87	1.054(0.56–1.985)
> 28	111(8.1)		1
Disease Characteristics
Tumor size		38(2.6)	0.788	0.959(0.709–1.298)
≤ 2cm	551(38.3)
2-5cm	778(54.1)
>5cm	109(7.6)
Histopathological staging		1(0.1)	0.002^**	1.439(1.138–1.819)
Stage 0	19(1.3)
Stage Ⅰ	368(24.9)
Stage Ⅱ	718(48.7)
Stage Ⅲ	357(24.2)
Stage Ⅳ	13(0.9)
ER		1(0.1)	0.956	1.017(0.552–1.875)
Negative	380(25.7)
Positive	1095(74.2)
PR		0(0)	0.473	1.339(0.603–2.973)
Negative	254(17.2)
Positive	1222(82.8)
HER2		0(0)	0.629	1.128(0.692–1.838)
Negative	493(33.4)
Positive	983(66.6)
Ki67		0(0)	0.286	1.296(0.805–2.086)
<25%	615(41.7)
>25%	860(58.3)
Lymph node metastasis		3(0.2)	0.006^**
No lymph node metastasis	862(58.5)		1
1–3 lymph node metastasis	339(23)		0.003	1.874(1.233–2.848)
4–9 lymph node metastasis	152(10.3)		0.071	1.673(0.958–2.923)
≥ 10 Lymph node metastasis	120(8.1)		0.009	2.141(1.208–3.794)
Treatment Characteristics
Surgical site		0(0)	0.132
Left	732(49.6)		0.222	3.424(0.475–24.66)
Right	710(48.1)		0.362	2.510(0.347–18.16)
Both sides	34(2.3)		1
Type of operation		0(0)	0.440	0.740(0.345–1.588)
Breast-conserving surgery	1359(92.1)
Mastectomy	117(7.9)
Sentinel-node biopsy		0(0)	0.027^*	0.461(0.232–0.914)
No	1172(79.4)
Yes	304(20.6)
Chemotherapy		0(0)	0.031^*	0.489(0.255–0.935)
Yes	1207(81.8)
No	269(18.2)
Radiotherapy		0(0)	0.002^**	0.535(0.361–0.792)
Yes	229(15.5)
No	1247(84.5)
Catheterization type		7(0.5)	0.020^*
Indwelling needle	429(29.2)		0.006	0.511(0.317–0.823)
PICC	334(22.7)		0.194	0.756(0.496–1.153)
TIVAPs	706(48.1)		1
Noted: P < 0.05,P < 0.01,**P < 0.001, BMI: body mass index, ER: estrogen receptor, PR: progesterone receptor, HER2: human epidermal growth factor receptor, PICC: peripherally inserted central catheter, TIVAPs: totally implantable venous access ports, CI: confidence interval

[Insert Table 1 here]

Table 1 also show the differences in the probability of developing lymphedema between the stratums of different risk factors, according to univariate analysis by the Kaplan-Meier method. Pre-hospitalization eating habits, histopathological staging, lymph node metastasis, sentinel node biopsy, chemotherapy, radiotherapy and catheterization type showed statistically significant differences (p < 0.05).

To further explore the effects of dietary habits and catheterization type on lymphedema, the variables that showed statistically significant differences in the univariate analysis are included in the multivariate analysis by Cox regression. The multivariate analysis results (Table 2) show that pre-hospitalization eating habits, catheterization type, radiotherapy and sentinel node biopsy had statistically significant differences (p < 0.05).

Table 2

Cox multivariate regression of factors predicting lymphedema
	B	SE	P-value	HR(95.0% CI)
Preoperative eating habits	0.905	0.237	0.000^***	2.473(1.554–3.936)
Radiotherapy	-0.545	0.203	0.007^**	0.580(0.390–0.862)
Sentinel-node biopsy	-0.785	0.351	0.025^*	0.456(0.229–0.908)
Catheterization type			0.034^*
TIVAPS vs Indwelling needle	-0.584	0.245	0.017	0.558(0.345–0.902)
TIVAPS vs PICC	-0.370	0.216	0.086	0.691(0.452–1.054)
Noted: P < 0.05,P < 0.01,P < 0.001, PICC: peripherally inserted central catheter, TIVAPs: totally implantable venous access ports, CI: confidence interval

[Insert Table 2 here]

Figure 2 shows the differences in the probability of developing lymphedema between stratums of pre-hospitalization eating habits, catheterization type, radiotherapy and sentinel-node biopsy. Patients with a high-fat diet pre-hospitalization showed a higher lymphedema incidence during the follow-up period (HR = 2.473; 95% confidence interval(CI) = 1.554–3.936; P < 0.001). Patients with TIVAPs showed a higher lymphedema incidence than patients with indwelling needle (HR = 0.558; 95%CI = 0.345–0.902; P = 0.017) and PICC (HR = 0.691; 95%CI = 0.452–1.054; P = 0.086). Patients with radiotherapy showed a higher lymphedema incidence during the follow-up period (HR = 0.580; 95%CI = 0.390–0.862; P = 0.007). Patients with sentinel node biopsy showed a lower lymphedema incidence during the follow-up period (HR = 0.456; 95%CI = 0.229–0.908; P = 0.025).

[Insert Fig. 2 here]

Our retrospective cohort included 1,476 patients who underwent surgery in our hospital. Of this total, 122 patients developed lymphedema with an incidence of 14.2% at five years follow-up and 15.8% at 10 years follow-up. This study found that dietary habits and catheterization type were independent risk factor for lymphedema in our study, however, contrary to expectations, the TIVAPs did not exert a protective effect on lymphedema, compared with the PICC.

In the 10-year follow-up cohort of patients who underwent surgical treatment for breast cancer, there was a cumulative lymphedema incidence of 15.8%. Although most lymphedema cases occurred in the first few years of the follow-up period, the cumulative incidence continued to increase throughout the evaluated years, consistent with a previous study [12]. A systematic review and meta-analysis found that the incidence of unilateral arm lymphedema post breast cancer treatment ranged from 8.4–21.4%, and the incidence of lymphedema in a retrospective study was relatively low [3]. The incidence of lymphedema in our study was consistent with a previous study, which reported an 8.4% incidence of lymphedema in the retrospective cohort [3]. There were three reasons for the relatively low incidence rate in our study: first, our department has arranged for professional case managers to conduct regular postoperative follow-up, supervision and health education for patients who undergo surgery in our department, which might have decreased the incidence of lymphedema in our department. Second, the department guides patients in doing functional exercises in the early stages after surgery, which is included in the nursing routine, and our department set out corresponding functional exercise locations and professional facilities for this to occur. In addition, we used patient self-reported methods to measure lymphedema. Previous studies have also shown that the sensitivity of self-reported lymphedema may be lower, because it depends on patient symptoms [3, 22]. Self-reported lymphedema could include discrepancies between judgments of whether there was lymphedema or mild lymphedema [19]. In other words, mild to no lymphedema might be reported, which could have resulted in a low incidence of lymphedema reported in our study. Thus, further research with additional measurement methods is needed, to study lymphedema and its independent risk factors more reliably.

As expected, a pre-hospitalization high-fat diet was an independent risk factor for lymphedema in our study. The probability of lymphedema for patients with a high-fat diet pre-hospitalization was 2.47 times greater than for those following a low-fat iet (HR = 0.558; 95%CI = 0.345–0.902; P = 0.017). Although few studies focused on the influence of eating habits on BCRL[23], previous studies found that alteration of serum phospholipid fatty acid composition is associated with secondary lymphedema in breast cancer survivors [24]. In additional, fatty acid composition can be influenced by dietary fat intake [24]. Thus, we assume that a high-fat diet might increase the incidence of secondary lymphedema occurrence in breast cancer survivors by influencing fatty acid composition. This result indicates that BCRL could largely be preventable through diet modification in breast cancer survivors, by reducing intake of a high-fat diet. Nurses and other healthcare professionals could encourage breast cancer patients to form the habit of following a low-fat diet to decrease the probability of lymphedema. On the other hand, while eating habits post-hospitalization are very different than eating habits pre-hospitalization, the effect of post-hospitalization eating habits on BCRL was not statistically significant in this study. Our study found only five patients followed unhealthy eating habits after their operation, as our department had arranged professional case managers and dietitians to follow up with patients who had undergone surgery in our department, including with postoperative diet planning and health education. This could have significantly modified the eating habits of breast cancer survivors and led to fewer patients following a high-fat diet after surgery. In addition, we assume that a small sample of patients following a high-fat diet post-hospitalization might lead to biased analysis results, so further study with a larger sample to identify the effect of post-hospitalization dietary habits on lymphedema is required.

We found that catheterization type was a statistically significant independent risk factor. The probability of lymphedema for patients with TIVAPs was 1.79 times that of those with indwelling needle (HR = 0.558; 95%CI = 0.345–0.902; P = 0.017), for limbs were limited in movement by the TIVAPs, more or less, which was indwelled in a limb for many months until the end of chemotherapy treatment. Although indwelling TIVAPs is an effective measure for preventing chemotherapeutic extravasation, one of the most serious complications of intravenous infusion chemotherapeutic drugs, TIVAPs is not the perfect indwelling method, and could increase the incidence of other complications, such as lymphedema. Contrary to expectations, the TIVAPs did not exert a protective effect on lymphedema, compared with the PICC, and the probability of lymphedema for patients with TIVAPs was 1.45 times that of PICC (HR = 0.691; 95%CI = 0.452–1.054; P = 0.086). In the department we studied, considering that right side is closer to superior vena cava than the left side and the complications on the right side were relatively less than on the left side, where the heart is located, the TIVAPs was indwelled in the right limb, no matter whether the right limb was affected. Previous studies have found that chemotherapy infusion in the affected limb was associated with lymphedema [12, 25]. Thus, we assumed that all TIVAPs indwelled in the right limb, no matter whether the right limb was affected or not, increased the incidence of lymphedema. This is because the right lymphatic drainage routes might have been damaged by cancer treatments, such as axillary lymph node dissection and radiation therapy, leading to fluid build-up and an increased risk of lymphedema [17, 26]. This result indicates that further research is needed to compare the incidence of lymphedema for a different TIVAPs catheter position, including the affected side and the healthy side. This study finding offers new insights into both the advantages and disadvantages of indwelling TIVAPs. Patients need to consider the position of TIVAPs, indwelling in either the affected side or the healthy side .

This study has the several obvious advantages of large sample size, long follow-up period and reliable data sources, recorded by professional case managers in our department. Our study also has some limitations. First, this is a retrospective study, which could only research the factors recorded in a database. The influence of a number of factors with no data recorded, such as exercise and surgery time length, on BCRL, remains unknown and was not examined in our study. Second, the assessment of lymphedema was based on patients’ self-reported lymphedema, which relied on clinically apparent, visible limb swelling, which the patient would seek care for and report to case managers. This approach often resulted in missed or delayed diagnosis. Future studies need to use more objectivity as well as accurate tools to diagnose lymphedema.

In conclusion, there was a cumulative lymphedema incidence of 15.8% in our 10-year follow-up cohort. Our study found that a pre-hospitalization high-fat diet was independent risk factors for lymphedema. Contrary to expectations, the TIVAPs did not exert a protective effect on lymphedema compared with the PICC. The results indicate that BCRL could largely be preventable through diet modifications, so nurses and other healthcare professionals could encourage breast cancer patients to develop the habit of following a low-fat diet to decrease the probability of developing lymphedema. In addition, the TIVAPs is still not a perfect indwelling method, which increases the incidence of lymphedema compared with the PICC. This finding indicate that nurses and other healthcare professionals need consider the increased risk of lymphedema due to indwelling TIVAP.

BCRL: Breast Cancer-Related Lymphedema

TIVAPs: Totally Implantable Venous Access Ports

PICC: Peripherally Inserted Central Catheter

HR: Hazard Ratio

BMI: Body Mass Index

CI: Confidence Interval

Ethics approval and consent to participate

This study was approved by the institutional review board of Xiangya 3rd Hospital, Central South University (Ref No. 2021-S065). Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable

Availability of data and material The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interests The authors have no relevant financial or non-financial interests to disclose.

Funding This work was supported by the Natural Science Foundation of Hunan province in China (Grant number: 2019JJ4047).

Authors’ Contributions LW: Conceptualization, Methodology, Project administration, Visualization, Writing; MZ: Data curation, Writing - review & editing; HL: Conceptualization, Methodology, Project administration, review & editing; HY: Data curation and Writing; JW: Data analysis and Writing - review & editing. BJ: Writing - review & editing; XC and JY: Following patients and data curation; BD: Writing – reviewing; DY: Data analysis. All authors have read and approved the manuscript.

Acknowledgments We thank the nursing interns in our department who assisted us in organizing the data.

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Effects of dietary habits and catheterization type on breast cancer-related lymphedema: a retrospective cohort study

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Version 1

Abstract

Figures

Background

Methods

Design, setting and population

Instruments for lymphedema measurement

Statistical analysis

Results

Discussion

Limitations

Conclusion

List About Abbreviations

Declarations

References

Status:

Version 1