According to the survey data from the International Agency for Research on Cancer (IARC), breast cancer (BC) accounted for 11.7% of all new cancer cases worldwide in 2020, and showed the highest incidence among all cancers (1). Six to eight cycles of chemotherapy over a total treatment period of 4-6 months are essential for systemic treatment in BC. For patients who require targeted therapy, the duration of treatment may be as long as a year. Notably, patients with advanced BC often require long-term maintenance therapy because of the erratic changes in their conditions, and their treatment duration may exceed one year (2).

Chemotherapeutic drugs are categorized into vesicant, irritant, and non-vesicant agents on the basis of the degree of vascular irritation (3). For example, the anthracyclines commonly used in BC chemotherapy, such as pirarubicin and epirubicin, are vesicant agents, and extravasation of these agents may cause tissue necrosis, tissue dysfunction, and permanent disfigurement of the port (4). Therefore, selection of the ideal vascular access that can be retained over long periods of time and does not adversely affect the vessels for BC chemotherapy is particularly important. A totally implantable venous access port (TIVAP) primarily consists of an injection seat for puncture and an intravenous catheter, and is suitable for infusion of high-concentration chemotherapy drugs and nutritional support therapy (5). In comparison with other central venous access devices such as the central venous catheter (CVC) and peripherally inserted central catheter (PICC), the catheter in TIVAP is unexposed on the body surface, making it convenient for patients’ routine life. Furthermore, since it is implanted deep in the body, it shows a low incidence of infection and is associated with a higher degree of safety, significantly improving the patient’s quality of life (6).

TIVAP has become the preferred intravenous infusion tool for patients with BC receiving chemotherapy. For patients at advanced stages or with a high risk of postoperative recurrence, retention of TIVAP during the non-treatment period, i.e., after the end of treatment, has been suggested, considering the need for retreatment in the event of disease recurrence. Although a seven-year retrospective study investigating 204 cancer patients suggested that long-term indwelling of TIVAPs is safe and cost-effective (7), retention of TIVAPs may cause complications such as infections, thrombosis, and catheter occlusion in some cases. Therefore, regular TIVAP flushing is essential to reduce the incidence of complications and maintain the functional integrity of the device.

The European Society of Medical Oncology (ESMO) guidelines recommend saline flushing and heparin sealing at four-week intervals in cases with insufficient scientific indications (8). The manufacturer’s instructions also recommend flushing the port every four weeks during the non-treatment stage (9), and this interval is widely adopted in current clinical practice. Nevertheless, the Infusion Nursing Society (INS) standards of practice for intravenous therapy (10) provide no definite recommendation for the optimal TIVAP flushing interval. Consequently, the optimal TIVAP flushing interval is debatable due to insufficient evidence.

Furthermore, existing studies have provided inconsistent findings supporting extended TIVAP flushing intervals during non-treatment periods (11). Several studies have reported that extended flushing intervals of more than 45 days, six weeks, eight weeks, three months, and four months are safe and feasible (12–16). However, most of the previous studies recommending short (e.g., 45 days, 6 weeks) and long flushing intervals (e.g., 3 and 4 months) have drawn their conclusions on the basis of small sample sizes consisting of patients with different tumor types and different disease states. Sang-Bo (17) conducted a retrospective analysis of 154 patients with colorectal cancer who underwent TIVAP-based chemotherapy, and their findings suggested that extending the flushing interval to three months is safe. Most of the research on extending the TIVAP flushing interval has focused on patients with gastrointestinal tumors, lung cancer, gynecologic tumors, and hematologic malignancies, with only a few studies exclusively focusing on extending the TIVAP flushing interval in patients with BC. Therefore, the optimal flushing interval for maintaining TIVAP patency during the non-treatment stage in patients with BC patients is still unclear.

Most of the existing BC-based TIVAP studies recommend flushing every 4 weeks (18, 19). However, almost all BC patients are recommended to be followed up at 3-month intervals during the first two years after surgery and at 6-month intervals during the third to fifth year (20). In this scenario, flushing intervals of 45 days, 6 or 8 weeks, and 4 months would require patients with TIVAP to visit the hospital or clinic specifically for TIVAP maintenance in addition to regular follow-up visits, undoubtedly increasing the inconvenience in patients’ routine life. The extension of the TIVAP flushing interval to three months in patients with BC would make it consistent with the periodicity of follow-up visits. Therefore, on the basis of the aforementioned evidence, we designed this study to review the differences, especially those related to complications, among patients who underwent TIVAP flushing at different intervals.

In this study, we conducted a retrospective analysis to explore the adverse events and complications associated with different TIVAP flushing intervals during the non-treatment stage in patients with BC. The current guidelines recommend a TIVAP flushing interval of approximately three months for most patients, which can facilitate TIVAP maintenance, although some patients voluntarily choose flushing intervals of one to two months. The incidence of TIVAP-related complications and TIVAP dysfunction under different flushing intervals was recorded to investigate the safety and feasibility of extending the TIVAP flushing interval.

This study retrospectively evaluated the feasibility and safety of extending the TIVAP flushing interval of patients with BC during the non-treatment phase. TIVAP is now widely used in chemotherapy and supportive care for malignancies. Yuejiao et al. (12) retrospectively analyzed the findings for 563 patients with malignant tumors whose TIVAP flushing intervals were extended beyond four weeks during the non-treatment period. They found that the complication rate in the extended group (>28 days) was not significantly different from that in the non-extended group (≤ 28 days) (p = 0.28), indicating the safety of extending the TIVAP flushing interval. Kefeli et al. (13) retrospectively analyzed patients who received chemotherapy for various malignancies (mostly gastrointestinal tract tumors); 30 of these patients underwent the standard flushing regimen (four weeks, 500 U heparin), whereas 59 underwent extended flushing intervals (six weeks, 1000 U). The one-year follow-up results indicated no infection or thrombosis in patients with extended flushing intervals, confirming that an extended flushing interval of to six weeks is safe and feasible.

A total of 14 flushing interval-related publications were included in the 2021 meta-analysis by Zhao-Yu et al. (21), which suggested that extending the flushing interval by eight weeks is safe and feasible. Six publications involving 1255 patients with various malignancies were included in the 2020 meta-analysis by Clari et al. (11), which also suggested that extending the flushing interval to four to eight weeks does not increase the incidence of TIVAP catheter-related obstruction and infection. The findings of our study are consistent with those obtained by Ignatov et al. (16), who demonstrated that extending the flushing interval to more than three months can effectively maintain TIVAP patency. Furthermore, numerous studies have reported extending the TIVAP flushing interval for more than four weeks, 45 days, six weeks, eight weeks, three months, and four months, and the findings of these studies suggested that extending the flushing interval for the corresponding time period is safe and feasible. However, an optimal TIVAP flushing interval has not yet been established. Therefore, prospective, multicenter, large-sample real-world studies are needed to validate our findings.

Thrombosis is one of the common TIVAP-related complications. TIVAP-related thrombosis is associated with surgery, infection, hospitalization, thrombogenic drug use, and the release of procoagulant substances from tumor cells in patients with malignancy (22). Venous thrombosis is usually asymptomatic or may occasionally present as pain or swelling. Kuo et al. (23) reported the findings for 73 gynecologic oncology patients whose flushing intervals were extended up to three months; among these patients, seven (7/73, 9.6%) had catheter tip-related thrombosis, with no significant difference in the incidence of thrombosis between the experimental and control groups. Heibl et al. (24) reported that among 143 patients with hematologic diseases whose flushing intervals were extended to four to six weeks, three (3/143, 2.1%) developed thromboses, including one case of deep venous thrombosis and two cases of catheter tip-related thrombosis. Ignatov et al. (16) conducted a retrospective study of 349 patients with malignant tumors who had undergone an extended flushing interval and found that eight patients developed catheter-related thrombosis, including three patients with deep venous thrombosis; the overall incidence of thrombosis in their study was 2.29%, and the difference between the experimental and control groups was not significant (P = 0.465).

Consistent with these findings, the present study included two cases of thrombosis, from groups 2 and 3, that were characterized by swelling of the affected limb and neck and subsequently confirmed by ultrasound. The patients received rivaroxaban treatment for 3 months as recommended, and the ports were finally removed (25). Our results indicated no significant difference in the incidence of thrombosis among the three groups (P = 0.22), suggesting that extension of the flushing interval did not increase the incidence of thrombosis. Notably, we did not perform routine thrombosis screening for all TIVAP patients in this study, so the incidence of asymptomatic thrombosis remains unknown.

Several studies have preliminarily explored whether an extended flushing interval increases the incidence of infection. Fornaro et al. (9) reported no significant difference in infection rate between a 4-week flushing group (2/106, 1.9%) and an 8-week flushing group (8/347, 2.3%; P = 0.80). A systematic literature analysis of four single-arm studies with a total of 925 patients (15, 26–28) reported that the incidence of infection associated with flushing at 6–12-week intervals was 1.6%. However, that study did not include a statistical analysis of the infection rate at different flushing intervals.

In this study, no significant differences were observed in the incidence of infection among the three groups (P = 0.42), and only two infectious cases manifesting as sudden-onset fever and chills were recorded. One case in group 1 was diagnosed as a Ralstonia pickettii infection, and the other case in group 2 was diagnosed as a coagulase-negative Staphylococcus infection. Both patients recovered quickly after receiving antibiotic treatment.

The source of infections attributable to intravenous catheters is mostly the microbial population in the skin around the catheter, and the most common bacteria causing TIVAP-related infections are coagulase-negative staphylococci, with Staphylococcus epidermidis, a common bacterial parasite of the skin and mucosa, being the predominant bacteria. Most patients develop infections in the first few months after TIVAP implantation, which may be because of surgery and chemotherapy and frequent punctures with atraumatic suture needles resulting in local skin bacterial infections (29). A low incidence of infection was observed in the present study. We hypothesized that this could be because most patients had undergone TIVAP implantation more than six months previously and had completed their treatment without many of the aforementioned risks. Overall, the results of this study and previous studies suggest that extending the flushing interval does not increase the incidence of infection.

Catheter obstruction, often defined as impaired pump-back or poor push injection, is another common TIVAP-related complication. The causes of TIVAP catheter-related obstruction can be divided into catheter- and non-catheter-related factors. Catheter-related factors include catheter compression, folding, improper end position, catheter displacement, and adherence of the catheter end to the vessel wall. Non-catheter-related factors include perfusion of nutritional drugs and drug interactions causing precipitation and obstruction. A meta-analysis (30) revealed that a TIVAP flushing interval beyond four weeks is safe, and extending the flush interval to eight weeks may not increase the incidence of catheter occlusion. Zhao-Yu et al. (21) included 1318 patients in a meta-analysis and divided them into a standard flushing group (four weeks) and an extended flushing interval group (>4 weeks); the incidence rates of catheter obstruction in these two groups were 3.7% and 4.2%, respectively (P = 0.29). In our study, no significant differences were observed in the incidence of catheter obstruction among the three groups (P = 0.24). The results of the abovementioned meta-analyses and the findings of our study indicate that extending the flushing interval does not increase the incidence of catheter occlusion, although relatively significant individual differences may be present. Jiaobo et al. (31) reported normal function of TIVAP after five years of disuse in one patient. Our center also had one patient with BC who did not undergo regular flushing. She received her first flush 24 months after her last chemotherapy due to BC recurrence, and her TIVAP remained functional.

The TIVAP should be flushed regularly to prevent the accumulation of fibrin or drugs. However, few studies have reported the effects of extended TIVAP flushing intervals on blood return. In this study, among the 617 patients who underwent TIVAP flushing during the non-treatment phase, 11 patients (1.78%) did not show blood return, while the remaining 606 patients (98.22%) showed blood return, with no significant difference in the blood return rate among the three groups (P = 0.42). Regular flushing is crucial to keep the TIVAP patent and functionally intact. However, evidence for the choice between saline and heparin flushing is unavailable. Heparin flushing is considered the most vital intervention to maintain TIVAP patency, prevent catheter obstruction, and reduce the risk of catheter-related infections (8). Several prospective studies in adult oncology patients have suggested that TIVAP maintenance with a 10-mL saline flush and a 5-mL heparin (100 U/mL) seal every three months is safe and effective (15, 28, 32). Solinas et al. (15) reported the findings for 381 patients with malignancy who received TIVAP implantation and underwent saline flushing every three months and suggested that flushing did not increase the risk of TIVAP obstruction. Rasero et al. (33) used saline to seal the catheters. However, heparin sealing was performed in most of the other studies, and it remains uncertain whether heparin is more effective than saline in sealing catheters (34, 35). In the present study, catheter sealing was performed using 5 mL of 100 U/mL sodium heparin. In a subsequent study, we aim to compare the difference between saline- and heparin-based catheter sealing and their effects on the extension of the TIVAP flushing interval.

Monthly flushing is time-consuming, inconvenient, and expensive. For patients with BC who are in the non-treatment period after treatment stabilization, doctors recommend reexamination every three months, which coincides with the TIVAP flushing interval. Therefore, extension of the TIVAP flushing interval can reduce the financial burden on patients and improve their quality of life. Furthermore, it can reduce the workload of healthcare workers and the consumption of medical supplies.

Nevertheless, this study had some limitations. First, it is a retrospective study with a relatively small sample size that may have resulted in selection bias. Therefore, we hope to design prospective, randomized controlled trials in the future to validate the findings of this study. Second, the difference between saline and heparin for catheter sealing during non-treatment TIVAP flushing and their effects on catheter obstruction were not evaluated. The catheters were sealed with heparin during all TIVAP flushes, which may have influenced our results. Finally, we may have overlooked asymptomatic intra-catheter thrombosis when assessing thrombotic complications due to the absence of routine vascular ultrasound examinations.

A retrospective analysis of 617 patients with extended flushing intervals during the non-treatment period revealed that extending the flushing interval to more than three months did not increase the incidence of complications such as infection, thrombosis, and catheter obstruction in comparison with the standard flushing interval commonly used in current practice. Therefore, extending the TIVAP maintenance interval to three months or beyond is a safe and feasible approach. This extension helped improve the efficiency of TIVAP maintenance, alleviated medical resource shortages to a certain extent, and reduced patients’ visit time.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Ethics Committee of the First Hospital Affiliated with the Army Medical University (Grant No.: (B) KY202253). The patients/participants provided their written informed consent to participate in this study.

Conception and design: YY, XQ, SH, HT. Data collection: LW, HF, XC, and JZ. Data analysis: YW, YZ. Writing and manuscript revision: YW, HT, YY. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.