Breast cancer recurrence and survival rates in patients who underwent breast‐conserving surgery under non‐mechanically ventilated anesthesia

Abstract Background Recurrence after primary treatment is an important obstacle to the curing of primary breast cancer. Less‐immunosuppressive anesthetic techniques, such as local anesthesia with lidocaine, intravenous anesthesia (IVA) with propofol, and/or sedation with midazolam under spontaneous breathing may reduce breast cancer recurrence compared with standard general anesthesia techniques such as IVA and inhalation anesthesia with opioids under mechanical ventilation. Aim The aim of this study was to analyze the factors involved in breast cancer recurrence in patients who underwent breast‐conserving surgery (BCS) under non‐mechanically ventilated anesthesia. Methods The study included 491 consecutive patients with stages 0–III breast cancer who underwent BCS/axillary lymph‐node management with local anesthesia and IVA and/or sedation under non‐mechanical ventilation between May 2008 and September 2021. Survival and recurrence were assessed by retrospective cohort analysis. Results The median follow‐up period was 2565 days (range, 28–4834 days). The overall and breast cancer–specific survival rates were 92.9% and 95.6%, respectively. Twenty‐one deaths, of which 11 were breast cancer–related, occurred. Disease recurred in 29 (5.9%) patients, of whom 15 patients received neoadjuvant chemotherapy (NAC) and 14 patients received adjuvant therapy (chemotherapy in 12 cases). The surgical procedure performed, but not other clinicopathological factors [recurrence site, P stage, tumor subtype, and disease‐free interval (DFI)], differed between the NAC and adjuvant therapy groups. The DFI tended to be shorter in the NAC group than in the adjuvant therapy group. The pathological therapeutic effect grade after NAC was 1 in 12 patients and ≥2 in 3 patients. Conclusion More than 50% (15/29) of patients with recurrence who underwent BCS were given NAC, but most patients did not respond to it. Similarly, adjuvant chemotherapy may not have contributed to the eradication of residual tumor cells after BCS. To reduce breast cancer recurrence in patients undergoing BCS, treatment strategies, especially for patients who do not respond to NAC or adjuvant chemotherapy, need to be developed. Non‐mechanical ventilation anesthesia may also affect the incidence of breast cancer recurrence.

strategies, especially for patients who do not respond to NAC or adjuvant chemotherapy, need to be developed. Non-mechanical ventilation anesthesia may also affect the incidence of breast cancer recurrence.

K E Y W O R D S
breast cancer, breast-conserving surgery, non-mechanical ventilation anesthesia, recurrence, survival

| INTRODUCTION
Over the past few decades, the development of systemic postsurgical therapies, such as anticancer drugs, molecular targeted drugs, and endocrine drugs, for a primary breast cancer has reduced breast cancer recurrence, and improved the patient survival rate. [1][2][3] In addition, with the discovery of tumor subtypes and the introduction of multi-gene assays, we can now select patients who will benefit from chemotherapy and individualize their treatment. 4,5 In contrast to the escalation of systemic therapies with neoadjuvant and adjuvant (e.g., dose-dense) chemotherapies, 6,7 surgical treatment has been deescalated from mastectomy and axillary lymph-node dissection (ALND) to breast-conserving surgery (BCS) and sentinel lymph-node biopsy (SLNB), even in locally advanced cases, with the use of neoadjuvant chemotherapy (NAC). 8 This paradigm shift is based on the concept that breast cancer is a systemic disease, and that micrometastases are released from the primary tumor via lymphatic and vessel channels. 9 In recent years, adjuvant molecularly targeted therapies with pertuzumab and trastuzumab for human epidermal growth factor 2 (HER-2)-positive breast cancer, 10,11 cyclin-dependent kinases 4 and 6 (CDK4/6) with abemaciclib for hormone receptor (HR)-positive/ HER-2-negative breast cancer, 12 and programmed cell death 1 with pembrolizumab for triple-negative (TN) breast cancer 13 have been developed to prolong invasive disease-free survival and to decrease morbidity associated with the primary breast cancer. Research indicates that these molecularly targeted agents can restore or enhance the drug sensitivity of some patients who do not respond well to anticancer or endocrine agents. [11][12][13] However, the recurrence of breast cancer, such as with distant metastasis, is seen infrequently during follow-up periods in clinical studies, meaning that the primary breast cancer has not been cured.
In general, breast cancer surgery is performed with standard forms of general anesthesia (GA), such as inhalation anesthesia with opioids or intravenous anesthesia (IVA) under mechanical ventilation.
However, breast cancer surgeries such as BCS and SLNB can be performed under non-mechanical ventilation with local anesthesia (LA; lidocaine) alone or in combination with propofol IVA and/or sedation with midazolam. [14][15][16] Propofol has been found to be less suppressive of cell-mediated immunity (CMI) than are inhalational anesthetics and opioids in mouse models and human samples, [17][18][19] and local anesthetics such as lidocaine have been shown to inhibit breast cancer growth in vitro and in vivo. 20 Furthermore, anesthesia with mechanical ventilation may induce cancer metastasis to the lungs and other parts of the body to a greater extent than does anesthesia with nonmechanical ventilation, as suggested by data from mouse models. 21,22 Thus, LA and IVA with propofol and/or sedative agents without ventilation may play a role in reducing breast cancer recurrence compared to GA with ventilation. With this background, we retrospectively evaluated the survival and breast cancer recurrence rates of patients who underwent BCS and ALN management with LA and IVA with propofol and/or sedative agents under non-mechanical ventilation in an outpatient setting.

| Patients
This retrospective study was performed with data from 491 women with a primary breast cancer (International Union for the Control of Cancer TNM stages 0-III) 23

| Anesthetic technique
LA with lidocaine, benzodiazepines (e.g., diazepam and midazolam) as sedatives, IVA with propofol, and pentazocine (an opioid receptor partial agonist) and pethidine (a synthetic opioid) as analgesics were used during the study period. Most frequently, each patient was given 30-80 ml 0.5% lidocaine in combination with IV propofol and/or midazolam. Preoperatively, 10 ml 0.5% lidocaine was injected locally into the posterior breast tumor space under ultrasound guidance when marking the tumor resection area; additional local injections were administered around the tumor before and during surgery. Pentazocine (15 mg) was administered as an analgesic. For intraoperative vital function monitoring, each patient was fitted with a biometric monitor to measure her pulse, electrocardiographic activity, blood pressure, respiratory rate, and oxygen saturation. In preparation for emergency mask ventilation and tracheal intubation, all patients were administered oxygen at a rate of 3-5 L/min by oxygen mask during surgery.

| Surgical procedure
All patients underwent BCS with partial or quadrant breast resection plus SLNB and/or ALND; BCS was defined as partial breast resection with resection of the primary tumor and a 1-1.5 cm margin.
Axillary SLNB was performed using indigo carmine and indocyanine green dyes. To evaluate SLN metastasis, one-step nucleic acid amplification (OSNA), 24 25 ALND has not been performed for metastases to one or two lymph nodes. Patients who received NAC and had no clinical lymph-node metastasis before chemotherapy underwent SLNB, and those with such metastasis confirmed by fine-needle aspiration biopsy before chemotherapy underwent SLNB or ALND in the absence of clinical lymph-node metastasis after chemotherapy.

| Anesthetic techniques and surgical complications
The anesthetic techniques used for BCS did not involve ventilation anesthesia; they were based on LA with lidocaine and are summarized Other techniques included the use of lidocaine alone or in combination with diazepam or midazolam and pentazocine or pethidine.
Regarding surgical complications, wound infection was observed in 16 (3.0%) patients, and postoperative hematoma was observed in 18 (3.6%) patients, 5 of whom underwent reoperation 5-7 days after surgery to stop bleeding at the resected site. Axillary lymphoceles were observed in 33 (7.2%) of the 84 patients undergoing limited ALND without axillary drainage; these lymphoceles disappeared after several aspirations, and no case required continued management after surgery.
Similarly, three cases of grade 1 TN breast cancer did not respond to NAC, and adjuvant therapy with oral fluoropyrimidine did not prevent recurrence.
Of the 14 cases of recurrence treated adjuvantly (e.g., with anticancer drugs and endocrine therapy), 7 recurred at 2-5 years after surgery ( In a preclinical study, however, mechanical ventilation during mastectomy under GA in mice implanted with breast cancer cell lines significantly increased the number of circulating breast cancer cells remaining in lung micrometastases and the incidence of postoperative lung metastasis. 21 Moreover, the paracrine secretion of proinflammatory cytokines may induce metastasis to organs other than the lung. 22 Although no evidence currently supports an effect of the anesthesia technique on the long-term prognoses of patients with breast cancer 46

FUNDING
No funding was received for this study.