Single dose of dexamethasone is not associated with postoperative recurrence and mortality in breast cancer patients: a propensity-matched cohort study

Even though surgery is the best curative option for solid tumours, surgical manipulation still carries a risk of tumour spreading. Even after complete removal, tumour cells released during surgery may eventually lead to recurrence if they escape immune surveillance [1‐3]. It is well known that corticosteroids induce generalized immunosuppression [4], and dexamethasone in particular can significantly suppress lymphokine production and cell proliferation [4], impair natural killer function [5, 6], and promote resistance to apoptosis in tumour cells [7].

However, many anaesthesiologists prefer to administer a single dose of dexamethasone because perioperative administration of this corticosteroid (4–10 mg intravenously) can reduce postoperative nausea/vomiting and surgical pain, and it can also enhance the quality of life during recovery, including the patient’s emotional state and physical independence [8, 9]. Despite its widespread use, there have been few clinical studies evaluating the influence of perioperative dexamethasone on oncological outcomes with conflicting results.

Breast cancer is one of the most common malignancies in women and is a leading cause of death globally. Although many studies on the treatment of breast cancer and prevention of postoperative recurrence have been performed, the 10-year survival rate in Western Europe is still 70% [10]. Therefore, it is necessary to investigate how dexamethasone, frequently used in the perioperative period, affects the outcomes of breast cancer, to address concerns about its immunosuppressive properties.

Dexamethasone is an effective and widely used agent that is administered perioperatively to improve the quality of recovery after surgery. However, dexamethasone can also induce immunosuppression and may cause tumour cells to escape from the immune system. As a patient’s perioperative management is only handled by the anaesthesiologist, the choice of anaesthetic agent may critically affect post-surgical outcomes. Hence, anaesthesiologists should consider the possibility of immunosuppression before administering dexamethasone. From this perspective, investigating the effects of perioperative dexamethasone administration on postoperative oncologic outcomes, in patients who were already immunocompromised due to the perioperative environment, is very important. In our study, we found that perioperative dexamethasone was not associated with recurrence or mortality of patients after breast cancer surgery.

Stress response following surgery is part of the systemic reaction to an injury, and it encompasses a wide range of immunological, endocrinological, and haematological effects [12]. Importantly, the inevitable immunosuppression during the perioperative period can allow tumour cells to evade the immune system, leading to recurrence in patients who are prone to undetectable micrometastases [13], even though surgical resection of a tumour remains the optimal curative treatment. Previous investigations suggest that perioperative impairment of the immune system increases the risk of cancer recurrence in patients undergoing oncologic surgery [14, 15]. Glucocorticoids are involved in postoperative suppression of natural killer cell activity [16]; their role in immunosuppression includes the significant suppression of lymphokine production and cell proliferation [4], impairment of natural killer function [6], and rendering tumour cells more resistant to apoptosis [7]. Glucocorticoids are also known to induce proliferation in normal cells such as erythroid progenitor cells and fibroblasts [17, 18]; and previous studies have shown that low concentrations of dexamethasone also can induce in vitro proliferation of cancer cells such as those derived from glioma [19], astrocytoma [20], and Kaposi’s sarcoma [21]. Hence, even though dexamethasone-induced immunosuppression may be temporary, it can aggravate tumour cell evasion of immune surveillance.

The issue of perioperative dexamethasone-induced immunosuppression influencing oncological outcomes has recently been investigated by other groups. Yu and colleagues retrospectively studied 515 patients who underwent rectal cancer surgery and found a higher rate of cancer recurrence in patients who received dexamethasone [22]. Moreover, patients receiving a single dose of dexamethasone before undergoing colon cancer surgery were shown to have a potentially increased risk of distant recurrence [23]. On the other hand, a retrospective study of 309 women who underwent endometrial cancer surgery showed that dexamethasone that was administered to prevent postoperative nausea and vomiting was not associated with an increased risk of cancer recurrence or with altered progression-free or overall survival compared to patients who did not receive dexamethasone [24]. Additionally, De Oliveira et al. [25] demonstrated that perioperative dexamethasone had no effect on recurrence in patients diagnosed with ovarian cancer, although they did not report survival data. Another study found that perioperative dexamethasone might improve postoperative survival in human pancreatic adenocarcinoma [26].

Our finding that perioperative dexamethasone appears to have no significant effect on postoperative outcomes including recurrence free and overall survival of patients who underwent breast cancer surgery may be explained as follows: Dexamethasone has been shown to reduce the perioperative stress response [27, 28]; therefore, the direct immunosuppression caused by dexamethasone may be counteracted by its protective effect on the normal stress response to surgical stimuli. Dexamethasone also has pro-apoptotic properties that may lengthen the survival of patients with certain types of cancer [29, 30]. Glucocorticoids can destroy cancerous lymphoid cells, and are thus essential for treating lymph node tissue malignancies.

In contrast to these favourable characteristics of dexamethasone, glucocorticoids in general may also induce the growth of malignant solid tumours and increase their dissemination as a consequence of decreasing inter-cell adhesiveness and enhancing tissue permeability. In this regard, two recent reports were published on the relationship between glucocorticoid use and breast cancer risk. They described no evidence of glucocorticoid use influencing breast cancer recurrence in Danish populations [31, 32]. However, these studies included breast cancer patients regardless of whether they underwent surgery, and also investigated various types of glucocorticoids combined. To the best of our knowledge, ours is the first study to investigate the impact of perioperative dexamethasone on postoperative recurrence and mortality in patients with breast cancer, and to determine whether single-dose dexamethasone is safe in patients undergoing breast cancer surgery.

Based on our findings, chemotherapy was not significantly associated with postoperative recurrence and mortality in the multivariate analyses, in contrast to univariate analysis results. This may be because of confounding effects associated with chemotherapy and TNM staging, as chemotherapy is administered according to the TNM stage in breast cancer patients. However, we could not avoid investigating chemotherapy and TNM stage together in our multivariate analysis model, as both were critical for determining the effect of dexamethasone on postoperative outcomes. Moreover, a higher TNM stage remained a critical risk factor for postoperative recurrence and mortality despite chemotherapy. Although the administration of dexamethasone to subjects with chemotherapy may lead to worsened prognoses in patients with breast cancer, it likely has little impact on the perioperative immunity of patients because surgery is usually scheduled 1 month after completing chemotherapy at our institution. Moreover, while the antiemetic regimen is prescribed according to the degree of nausea experienced by patients, dexamethasone is not a routinely administered agent. Furthermore, a large cohort study of breast cancer patients [32] showed no evidence of an association between preoperative systemic, inhaled, or intestinal-acting glucocorticoids and breast cancer recurrence. As our study was designed to investigate the effect of a single dose of dexamethasone during anaesthesia on oncologic outcomes, we did not include the data of dexamethasone administered for neoadjuvant chemotherapy. Additionally, we performed sub-group analyses to find out more association between dexamethasone and subtypes of breast cancer such as ER-dependency, PR-dependency, or TNM staging. In this result, we found that dexamethasone is associated with the risk of mortality in PR-dependent breast cancer and recurrence in TNM stage 1 after breast cancer surgery. This detrimental effect of dexamethasone in TNM stage 1 and PR-dependent breast cancer requires further studies with sufficient sample size.

The present study is limited by its retrospective nature. Our patients were not randomised, and the clinical protocol was not standardised; therefore, selection bias and the effects of unmeasured confounding variables cannot be excluded. Moreover, the factors that influenced care providers to administer or forgo perioperative dexamethasone are unknown, although such decisions were unlikely to be associated with tumour status. Even though single-dose perioperative dexamethasone administration has known to have no association with an increased risk of acute postoperative complications including wound infection, the lack of information regarding dexamethasone-related adverse effects other than recurrence or mortality was considered a weak point of the study. There may be limited strength to the conclusion because of the relatively small population who received dexamethasone compared with the large total sample size. Nevertheless, the reliability of our data was buttressed by the retrospective design to some extent, because our homogeneous patients comprising 2628 women were managed perioperatively in a similar manner at the same hospital. Above all, our analyses may have the statistical power by the sensitivity test of 1-to-5 propensity score matching, which led to well-matched groups and minimized the potential for significant confounding. Although randomised clinical trials are required for definitive conclusions, our results from post-propensity score matching ought to add valuable insight despite the study’s limitations.

In conclusion, our results suggest that a single dose of perioperative dexamethasone does not increase the risk of recurrence in patients after breast cancer surgery, and it appears to be safe in this patient population.