
==== Front
J Breast Cancer
J Breast Cancer
JBC
Journal of Breast Cancer
1738-6756
2092-9900
Korean Breast Cancer Society

39228156
10.4048/jbc.2024.0122
Original Article
The Risk of Deep Vein Thrombosis and Optimal Timing of Breast Cancer Surgery After COVID-19 Infection
https://orcid.org/0000-0001-9546-1704
Bi Zhao *
https://orcid.org/0009-0005-2028-4631
Cheng Wei-Hao *
https://orcid.org/0009-0009-7221-5610
Wang Wei-Li
https://orcid.org/0009-0002-1134-1815
Wang Yong-Sheng
Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Correspondence to Yong-Sheng Wang. Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan 250000, China. yswang@sdfmu.edu.cn
Correspondence to Wei-Li Wang. Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan 250000, China. 382390582@qq.com
*These authors contributed equally to this work.

8 2024
21 8 2024
27 4 281288
10 5 2024
05 7 2024
11 8 2024
© 2024 Korean Breast Cancer Society
2024
Korean Breast Cancer Society
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Purpose

The aim of this study was to assess the risk of postoperative deep vein thrombosis (DVT) in breast cancer patients with coronavirus disease 2019 (COVID-19) to determine the optimal timing for surgery in the era of “post COVID-19 pandemic.”

Methods

This prospective study included breast cancer patients who contracted COVID-19 and underwent surgery from December 20th, 2022, to March 20th, 2023 (n = 577). A control group comprised patients who underwent surgery from May 1st, 2019, to October 1st, 2019 (n = 327) and had not contracted COVID-19 prior to surgery. Patients were categorized based on the timing of their surgery relative to their COVID-19 infection. Data were analyzed using logistic regression.

Results

Patients with COVID-19 had a higher incidence of postoperative DVT compared to those without COVID-19 (3.64% vs. 1.21%). Multivariable logistic regression analysis indicated that the timing of surgery was significantly associated with the risk of DVT (odds ratio [OR], 2.795; 95% confidence interval [CI], 0.692–11.278; p = 0.024). Patients who underwent surgery within two weeks of COVID-19 infection experienced the highest DVT rates (OR, 10.556; 95% CI, 1.095–303.313; p = 0.003). However, the incidence decreased to 2.85% when surgery was delayed until two weeks or more after infection. The median follow-up period was 10 months, all patients with DVT after surgery were recovered without serious complications or death. There were no adverse effects on subsequent anti-tumor therapy.

Conclusion

Caution is advised when performing breast cancer surgery within two weeks after a COVID-19 infection. Although the risk of DVT remains somewhat elevated even after two weeks, surgery can be considered safe given the urgency of treatment, favorable complication outcomes, and lack of impact on subsequent adjuvant therapy.

Breast Neoplasms
COVID-19
Postoperative Complications
Time Factors
Venous Thrombosis
Key Technology Research and Development Program of Shandong Province https://doi.org/10.13039/100014103 2021SFGC05012021
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pmcINTRODUCTION

As of May 2023, the World Health Organization determined that coronavirus disease 2019 (COVID-19) is now an established and ongoing health issue and no longer constitutes a public health emergency of international concern [1]. Patients with cancer are particularly susceptible to COVID-19 due to the systemic immunosuppressive state induced by the malignancy and anticancer treatments [2]. Breast cancer accounts for almost one-third of all new cancer diagnoses in women [3], resulting in a substantial number of patients with breast cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During the COVID-19 pandemic, surgeries for breast cancer were frequently postponed. In the “post COVID-19 pandemic” era, there has been a shift towards focusing on the preoperative evaluation of patients infected with the virus, the timing of surgery, and the prevention of postoperative complications [4].

Previous studies have shown that a preoperative COVID-19 infection is associated with significantly increased risks of postoperative complications [5678910]. As one of the serious postoperative complications, postoperative deep vein thrombosis (DVT) is a venous disorder disease caused by abnormal blood clotting in deep veins, and the main adverse consequences are pulmonary embolism and post thrombotic syndrome, which can significantly affect the quality of life of patients and even lead to death. Cancer represents a strong risk factor for the development of cancer-associated thrombosis, with an estimated increased risk of DVT 4 to 6.5 times higher than in people without cancer.

The postoperative DVT of breast cancer surgery may differ from those of other types of surgery [11]. Compared with gastric cancer and pancreatic cancer patients, the risk of DVT in breast cancer patients is relatively low, with an incidence of 0.3% to 3.2%. The optimal timing for breast cancer surgery after a COVID-19 infection remains controversial. Therefore, breast cancer patients infected with COVID-19 require individualized preoperative evaluations, and various factors must be comprehensively assessed to determine the optimal timing for surgery. The objective of this study was to assess the association between the timing of surgery in relation to COVID-19 infection and the risk of postoperative DVT of breast cancer patients, then we want to identify the best timing for breast cancer surgery following a COVID-19 infection.

METHODS

Study population

Before December 2022, COVID-19 was classified as a category A infectious disease. After December 2022, our country downgraded COVID-19 to a category B infectious disease [12]. Consequently, government controls on the infected population were relaxed, leading to a surge in COVID-19 cases similar to trends observed globally. Therefore, breast cancer patients diagnosed with COVID-19 between December 20th, 2022, and March 20th, 2023, were included in the study. Due to the small number of patients who did not contract COVID-19 during the same period in our hospital, we selected cases from May 1st, 2019, to October 1st, 2019, as the control group. These patients had not been infected with COVID-19 prior to their surgery, ensuring that any postoperative complications could not be attributed to the sequelae of a COVID-19 infection.

The date a patient was confirmed to have COVID-19 in this study cohort was defined as the date of their first positive reverse transcription polymerase chain reaction test for COVID-19 [13]. COVID-19 severity was categorized as mild, moderate (accompanied by pneumonia), and severe (e.g., requiring supplemental oxygen) [1213]. All patients were vaccinated against SARS-CoV-2 prior to surgery.

The study protocol was approved by the Institutional Review Board of the Shandong Cancer Hospital (No. SDTHEC20220324) and was conducted in accordance with the principles of the Declaration of Helsinki. All methods were carried out in line with applicable guidelines and regulations. Written informed consent was obtained from all patients for the publication of this study and any accompanying images.

Study cohort design

This study was a single-center, prospective observational study. Patients were categorized into six groups based on the timing of their surgery after a COVID-19 infection: 1) The “peri COVID-19” group, with surgery performed 0–2 weeks after COVID-19 infection. 2) Patients who underwent surgery 3–4 weeks after infection. 3) Patients who underwent surgery 5–6 weeks after infection. 4) Patients who underwent surgery 7–8 weeks after infection. 5) The “post COVID-19” group, with surgery performed more than 8 weeks after infection. 6) The “pre COVID-19” control group, consisting of patients who had not been infected with SARS-CoV-2 before surgery and any 30-day postoperative complications they developed could not be attributed to the sequelae of COVID-19 infection.

Complications

The primary outcome of interest for the present study was the rate of postoperative DVT in the six months after surgery. The clinical presentation of DVT varies depending on the extent and location of the thrombus, with cardinal signs and symptoms including asymmetrical swelling, warmth, or pain in an extremity. Ultrasound examinations indicated emboli formation in the blood vessels.

We analyzed the rate of DVT across different groups. Concurrently, we followed up with patients who developed DVT and analyzed their outcomes.

Statistical analysis

The characteristics and unadjusted outcomes of patients were assessed using Pearson χ2 test for categorical variables. Univariate analysis of categorical variables was performed using the Pearson χ2 test or Fisher's exact test, including tumor stage (T stage, N stage), timing of surgery relative to COVID-19 diagnosis, mode of operation, concomitant syndromes, etc. Multivariable logistic regression analysis was conducted to identify independent predictive factors of DVT using backward stepwise regression.

Statistical analyses were performed using SPSS Statistics 22.0 software (IBM Corporation, Armonk, USA) and R version 3.3.3 software (The R Foundation for Statistical Computing, Vienna, Austria). A p < 0.05 was considered statistically significant.

RESULTS

The characteristics of enrolled patients

The consort diagram of the study is illustrated in Figure 1. From December 20th, 2022, to March 20th, 2023, 640 patients underwent surgery following a COVID-19 infection. After excluding 63 patients who underwent neoadjuvant therapy, 577 patients who had surgery post COVID-19 infection were included in this retrospective study. Of the patients infected with SARS-CoV-2, 51, 87, 99, and 150 patients underwent surgery 0–2, 3–4, 5–6, and 7–8 weeks after their COVID-19 diagnosis date, respectively. A total of 190 patients underwent surgery eight weeks or more after their COVID-19 diagnosis date. An additional 329 patients who underwent surgery between May 1, 2019, and October 1, 2019, and had not been infected with COVID-19 before surgery, served as the control group. Thus, any postoperative complications in this group could not be attributed to sequelae of COVID-19 infection. The basic clinical and pathological characteristics of the enrolled patients are summarized in Table 1.

Figure 1 Consort diagram of the study.

COVID-19 = coronavirus disease 2019.

Table 1 Clinical characteristics of the patients

Characteristics	Pre COVID-19 surgery before Oct. 1, 2019	Peri COVID-19 surgery 0–2 wk after COVID-19	Early post COVID-19 surgery 3–4 wk after COVID-19	Early post COVID-19 surgery 5–6 wk after COVID-19	Early post COVID-19 surgery 7–8 wk after COVID-19	Late post COVID-19 surgery > 8 wk after COVID-19	
Age (median)	49	49	49	45	44	50	
Clinical N stage							
	cN0	226 (68.7)	33 (64.7)	39 (44.8)	76 (76.7)	90 (60.0)	107 (56.2)	
	cN1	72 (21.9)	15 (29.4)	30 (34.6)	7 (7.1)	45 (30.0)	50 (26.6)	
	cN2	13 (3.9)	3 (5.9)	9 (10.3)	10 (10.1)	12 (8.0)	21 (10.8)	
	cN3	18 (5.5)	0 (0.0)	9 (10.3)	6 (6.1)	3 (2.0)	12 (6.4)	
Clinical T stage							
	cT1	206 (62.6)	21 (41.2)	30 (34.6)	61 (61.6)	69 (46.0)	103 (54.3)	
	cT2	116 (35.3)	27 (52.9)	48 (55.1)	26 (26.3)	66 (44.0)	79 (41.5)	
	cT3	3 (0.9)	0 (0.0)	9 (10.3)	9 (9.1)	3 (2.0)	5 (2.6)	
	cT4	4 (1.2)	3 (5.9)	0 (0.0)	3 (3.0)	12 (8.0)	3 (1.6)	
Breast surgery							
	Mastectomy	259 (78.7)	27 (52.9)	66 (75.8)	60 (60.6)	111 (74.0)	119 (62.6)	
	BCS	70 (21.3)	24 (47.1)	21 (24.2)	39 (39.4)	39 (36.0)	71 (37.4)	
Concomitant syndromes							
	Hypertension	33 (10.0)	6 (11.8)	15 (17.2)	9 (9.1)	18 (12.0)	19 (10.0)	
	Diabetes	7 (2.1)	3 (5.9)	0 (0.0)	1 (3.0)	6 (4.0)	10 (5.2)	
	Liver disease	20 (6.1)	3 (5.9)	0 (0.0)	0 (0.0)	0 (0.0)	2 (1.1)	
	Stroke	2 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	2 (1.1)	
	CAD	1 (0.3)	0 (0.0)	3 (3.4)	0 (0.0)	0 (0.0)	3 (1.5)	
COVID-19 severity							
	Mild/moderate	NA	48 (94.1)	84 (96.5)	99 (100.0)	147 (98.0)	189 (99.5)	
	Severe	NA	3 (5.9)	3 (3.5)	0 (0.0)	3 (2.0)	1 (0.5)	
Values are presented as number (%).

COVID-19 = coronavirus disease 2019; BCS = breast conserving surgery; CAD = coronary artery disease; NA = not available.

The majority of patients experienced mild COVID-19 symptoms; only eight patients (1.38%) had moderate COVID-19 (pneumonia). Interestingly, these eight patients with mild COVID-19 did not experience complications after surgery. Most patients had a temperature below 39°C, with 7.2% experiencing temperatures above 39°C. Across all groups, the most common comorbidities were obesity, diabetes, and hypertension. Mastectomy was the most common surgical procedure performed in both the pre COVID-19 and post COVID-19 groups.

The incidence of DVT after surgery

The incidence of postoperative DVT for each group is detailed in Table 2. All identified DVTs were classified as intermuscular venous thrombosis. Patients with peri-operative COVID-19 infection had the highest rates of DVT (11.76%) compared to other groups, while the incidence decreased to 2.85% when surgery was performed two weeks or more after their COVID-19 diagnosis. Patients who underwent surgery eight weeks or more after their COVID-19 diagnosis had a similar incidence of postoperative DVT compared with the pre COVID-19 group.

Table 2 Postoperative deep vein thrombosis after breast cancer surgery in different groups

Groups	DVT	
Pre COVID-19 surgery before Oct. 1, 2019 (n = 329)	4 (1.21)	
Surgery 0–2 wk after COVID-19 (n = 51)	6 (11.76)	
Surgery 3–4 wk after COVID-19 (n = 87)	3 (3.45)	
Surgery 5–6 wk after COVID-19 (n = 99)	3 (3.03)	
Surgery 7–8 wk after COVID-19 (n = 150)	6 (4.00)	
Surgery > 8 wk after COVID-19 (n = 190)	3 (1.58)	
Values are presented as number (%).

DVT = deep vein thrombosis; COVID-19 = coronavirus disease 2019.

Patients infected with COVID-19 had a higher incidence of DVT after surgery compared to those without COVID-19 infection (3.64% vs. 1.21%). The incidence of DVT was 3.57% in patients who underwent surgery 3–8 weeks after their COVID-19 diagnosis and 4.65% in those who had surgery within eight weeks after their diagnosis.

Univariate analysis indicated that the timing of surgery was significantly associated with the incidence of DVT (Table 3). The incidence of DVT in patients with peri COVID-19 infection was significantly higher than in other groups. Multivariable logistic regression analysis demonstrated that the timing of surgery was a significant factor associated with DVT (odds ratio [OR], 2.795; 95% confidence interval [CI], 0.692–11.278; p = 0.024). Patients who underwent surgery within two weeks after COVID-19 infection had the highest risk of DVT (OR, 10.556; 95% CI, 1.095–303.313; p = 0.030) compared to other groups.

Table 3 Univariate analysis of postoperative deep vein thrombosis

Characters	DVT	Univariate p-value	Multivariate p-value	
Yes	No	
Age (yr)			0.541		
	< 50	12	437	
	≥ 50	13	444	
Clinical N stage		0.094		
	cN0	12	559	
	cN1	6	213	
	cN2	5	63	
	cN3	2	46	
Clinical T stage			0.627		
	cT1	14	476	
	cT2	8	354	
	cT3	3	26	
	cT4	0	25	
Breast surgery			0.558		
	Mastectomy	18	624	
	BCS	7	257	
Groups			0.008	0.024	
	Pre COVID-19	4	325	
	0–2 wk	6	45	
	3–8 wk	12	324	
	> 8 wk	3	187	
DVT = deep vein thrombosis; BCS = breast conserving surgery; COVID-19 = coronavirus disease 2019.

We analyzed the correlation between the severity of COVID-19 infection and postoperative DVT. Although the results indicated a trend, the difference was not statistically significant (p = 0.497).

The result of follow-up

We conducted follow-up for patients with COVID-19 who experienced complications after surgery. The median follow-up period was 10 months, ranging from 9 to 12 months. The 21 patients with DVT received treatment that included elevation of the affected limb, thrombolytic therapy, and conventional anticoagulation. All patients recovered after continuous treatment and completed their therapy. There were no serious complications or deaths, and no adverse effects on subsequent anti-tumor therapy were observed.

DISCUSSION

In this study, we assessed the relationship between the timing of surgery after COVID-19 infection and the risk of postoperative DVT in 577 patients undergoing major breast cancer operations. The incidence of DVT fell within acceptable limits when surgery was performed two weeks or more after their COVID-19 diagnosis. Additionally, all patients with complications safely recovered from their treatments. It is suggested that the overall benefits of surgery after COVID-19 outweigh the risks of complications caused by the infection. Therefore, in the “post COVID-19 pandemic” era, caution is advised when performing elective breast cancer surgery within two weeks of a COVID-19 infection (“peri COVID-19”). Although the risk of DVT remains slightly elevated when surgery is conducted two weeks after a COVID-19 infection, surgical treatment can be recommended due to the urgency of breast cancer treatment, the favorable prognosis of complications, and the absence of impact on subsequent adjuvant therapy.

The risk of DVT in cancer patients is higher than that in non-cancer patients. Compared with gastric cancer and pancreatic cancer patients, the risk of DVT in breast cancer patients is relatively low. At present, the acceptable incidence of DVT after breast cancer surgery has not received an international consensus, and several studies have shown that the incidence of DVT after breast cancer surgery is 0.16%–3.2% [141516]. The COVID-19 Surg Collaboration performed studies to determine the risk of DVT within 30 days after surgery in patients with perioperative or prior COVID-19 infection. The incidence of postoperative DVT is 0.5% in non-COVID-19 patients, and 2.2% in patients within four weeks after COVID-19 infection [17]. The incidence of DVT in patients with previous COVID-19 infection is 1.0%. While in our study, the incidence of postoperative DVT is 1.21% in non-COVID-19 patients, and patients within two weeks after COVID-19 infection had the highest rates of DVT (11.76%). The incidence was decreased into 2.67% when surgery two weeks or more after their COVID-19 diagnosis date. Therefore, in the era of “post-pandemic,” it needs to be cautious when elective breast cancer surgery was performed within two weeks after the COVID-19 infection (“peri COVID-19”). Breast cancer surgery might be safely performed two weeks or more after COVID-19 diagnosis date in patients with mild to moderate COVID-19 infection, in order to prevent progression of disease. Patients with breast cancer surgery should be record the history of COVID-19 infection in detail, and thrombosis risk need to assessed timely. At the same time, the basic preventive measures should also be taken to prevent venous thromboembolism according to the condition, using mechanical preventive measures such as anti-thrombotic socks and intermittent pneumatic compression devices if necessary [181920]. DVT should be actively prevented in breast cancer patients who have surgery within eight weeks of COVID-19 infection.

This study has several limitations. First, the single-center observational design may introduce patient selection bias, and the small number of patients in peri-operative stages precluded matching by propensity score. Further multi-center studies with larger patient groups are necessary to validate these findings. Second, the low number of moderate to severe cases limits the applicability of conclusions to primarily mild cases. Additionally, this study focused solely on breast cancer surgery, which may restrict the broader applicability of the findings. Third, the follow-up duration was insufficient. Lastly, as SARS-CoV-2 may heighten the risk of DVT by inducing immune thrombosis, further basic research is required to confirm whether COVID-19 infection directly causes thrombosis.

In conclusion, in the “post COVID-19 pandemic” era, breast cancer surgery may be safely conducted two weeks or more after a COVID-19 diagnosis in patients with mild infections, helping to prevent disease progression.

Funding: This work was supported by grants from The Key Research and Development Program of Shandong (Major Science and Technology Innovation Project 2021SFGC05012021).

Conflict of Interest: The authors declare that they have no competing interests.

Data Availability: The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Author Contributions: Conceptualization: Bi Z, Cheng WH, Wang YS.

Data curation: Bi Z, Cheng WH, Wang WL.

Formal analysis: Bi Z, Cheng WH, Wang WL.

Resources: Wang YS.

Writing - original draft: Bi Z, Wang WL, Wang YS.

Writing - review & editing: Bi Z, Wang YS.
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