Comparison of volatile/inhalational and IV anesthesia in long-term survival of patients with breast cancer: a retrospective study
European Journal of Medical Research volume 27, Article number: 271 (2022)
Breast cancer is a worldwide health concern, and surgical removal has remained the preferred therapeutic option in most patients. Furthermore, the current study was designed to investigate the disease-free survival and overall survival in breast cancer patients, who receive either propofol or isoflurane during operation.
This retrospective study was conducted on 994 patients (IV group, n = 530; volatile/inhalational group, n = 464) who underwent breast cancer operation from January 2006 to December 2016 at Faghihi Hospital, Shiraz, Iran. All studied patients were followed up till 2020. Patients are classified into two groups, IV and volatile/inhalational, according to the received anesthesia. For statistical analysis, The Cox regression test was conducted to investigate the association between factors affecting the recurrence of the disease and the Log Rank test was utilized to assess the patients’ survival. Finally, to reduce the effect of confounding factors, all patients were matched according to age, tumor size and tumor grade.
Based on results from the log-rank test, the volatile/inhalational group had a better recurrence-free survival (P = 0.039) compared to the total IV group. However, the overall survival was not considerably different (P = 0.520).
The current study showed that although 2-year disease-free survival is higher in the volatile/inhalational group, there is no meaningful association between the 5-year overall survival and anesthesia technique.
Breast cancer is a global health concern, and it is the most prevalent cancer in women [1, 2]. In addition, breast cancer is the major cause of cancer death in women, responsible for more than five percent of all cancer mortality [1, 3]. Surgical removal of breast cancer remains a mainstay of curative-intent treatment in addition to chemotherapy and radiotherapy [4, 5]. Despite the evident impacts of surgical resection, the operation itself may release the tumor cells into the blood circulation. These tumor cells which are spread during the surgical manipulation may result in metastasis in many patients [3, 6].
Local recurrence or distant metastasis following the initial tumor resection remains a main therapeutic challenge . The likelihood of breast cancer recurrence is multifactorial. Various factors that impact the possibility of metastasis or recurrence, are possible remaining cancer cells of the surgical margin, the type of the cancer cells, and the patient’s immune system . In addition, various predisposing factors such as type of anesthesia, opioid analgesics and physiologic stresses may weaken the immune system and thus accelerate possible metastasis [8, 9]. In this regard, the surgical resection of the tumor may disseminate tumor cells into the vessels [10, 11]. Furthermore, the surgical stress response to tumor removal may trigger the blood cells to release various proinflammatory cytokines, which may impair the immune system, leading to the survival of residual tumor cells, resulting in further metastasis or recurrences .
Conventionally, the general anesthesia is established either through administering the volatile inhalational anesthetic which is a halogen-containing hydrocarbon or propofol, which is given intravenously . The present study aimed to assess the overall survival and disease-free survival after surgery in breast cancer patients receiving propofol or isoflurane during the operation.
Materials and methods
The present retrospective cohort study was conducted in Shiraz Breast Clinic, Shiraz, Iran. The mentioned center is the main referral clinic for patients with breast cancers in the South of Iran. In the current study, the clinical data of patients with the impression of Invasive ductal carcinoma who underwent breast cancer surgery were assessed between 2006, and 2016. All studied patients were followed up till 2020. Patients were excluded from the study if met the following criteria: bilateral breast cancer, immediate breast reconstruction surgery, metastatic breast cancer, other malignancy, history of breast surgery, administration of both IV and inhalation anesthetics, male gender, benign breast tumor or carcinoma in situ, American Society of Anesthesiologists  physical status greater than or equal to IV, and unknown type of anesthesia or receiving local and regional anesthesia. Patients were categorized based on the received anesthesia into the Total IV (IV group which was treated with continuous infusions of propofol and remifentanil) or volatile/inhalation anesthesia (the volatile/inhalational group which was treated with sevoflurane or isoflurane) and additional analgesic opioids if necessary. The administered anesthesia was selected by the attending anesthesiologists based on the patient’s condition.
Variables and outcome measurements
The following data were obtained from the recorded data in the breast cancer registry: surgery type, recurrence condition, pre- or post-operation adjuvant chemotherapy, administered radiotherapy or endocrine therapy, invasion condition, tumor size, estrogen and progesterone receptor status, histological tumor grade, histopathological type of tumor, epidermal growth factor receptor type 2 (HER-2) expression, and level of axillary node involvement.
Data regarding the type and the dose of administered analgesics and opioids were gathered through reviewing the hospital records of patients who underwent surgery in Shahid Faghihi hospital affiliated with Shiraz University of medical science. The duration of the operation, duration of anesthesia, and date of surgery were also noted. In this study for reducing the effect of the confounding factors, all the patients were matched according to age, tumor grade, tumor size and hormonal receptor.
The current study results are described as the number and percentage for categorical variables and as the mean ± SD for continuous variables. At first, the normality of the variables was checked through the Kolmogorov–Smirnov test. Considering that the significance value was greater than 0.05. Therefore, all variables have a normal distribution. The independent samples T-test was utilized to assess continuous variables. Also, the Chi-square test was applied in a bid to investigate categorical variables between groups.
In this cohort study, recurrence-free survival and overall survival were calculated for up to 2 and 5 years by conducting the Kaplan–Meier method, and the groups were compared by the log-rank test. The full Cox proportional hazards models were utilized for univariate and multivariate analysis of variables influencing recurrence of breast cancer; potential risk factors such as age, duration of anesthesia, type of anesthesia, involvement of right or left breast, tumor size, tumor grade, in situ component, tumor necrosis, type of lymph node involvement, margin involvement, axillary management, ER, PR, Her2, neoadjuvant and adjuvant chemotherapy, radiotherapy, IORT, and hormone therapy. In addition, backwards multivariable selection were performed. In the backward selection method, all predictive variables are first entered into the equation, and then if they do not meet the criteria to remain in the model, they are removed one by one from the model. Furthermore, the considerable variables (P < 0.5) of univariate analysis were considered in multivariate analysis. At the end of this statistical analysis, propensity score matching was applied to decrease the possible confounding impacts of each variable and the variances in baseline characteristics between the groups. The variables used for matching were age, tumor size, and tumor grade. The applied matching method were propensity score matching. It should be noted that these variables were selected based on the previous literature. In this regard, the result of match analysis was like that of the initial analysis. All statistical analyses were conducted with SPSS software version 25.
Of all patients who went under breast cancer operations from January 2006 to December 2016 at Faghihi Hospital, 994 patients (IV group, n = 530; volatile/inhalational group, n = 464) were selected for the analyses. The demographic characteristics of studied patients are depicted in Table 1. Breast cancer prognostic factors are shown in Table 2. There were meaningful differences among the propofol group and the sevoflurane group in the duration of follow-up, time to recurrence, axillary management, multi-focal tumor, distribution of estrogen and progesterone receptors, and IORT. The mean follow-up duration was 68.01 (interquartile range, 57.43–78.60) months for the volatile/inhalational group, and 48.83 (interquartile range, 41.36 to 56.30) months for the IV group.
In addition, the Cox regression analysis was applied in a bid to identify risk factors associated with cancer recurrence. Variables associated with the recurrence of breast cancer are demonstrated in Tables 3 and 4. The meaningful variables in univariate analysis were considered as age, type of anesthesia, tumor size greater than 5 cm, tumor grade III, ALND, ER, PR, neoadjuvant chemotherapy, and hormone therapy. In multivariate analysis of significant variables, tumor size and neoadjuvant chemotherapy remained meaningful risk factors for recurrence after operation.
Based on results from the log-rank test, the volatile/inhalational group had a better recurrence-free survival (P = 0.039) compared to the propofol group. However, the overall survival was not considerably different (P = 0.520) (Table 5, Figs. 1 and 2). Table 6 indicates the 2-year recurrence-free survival rates and 5-year overall survival rates for the IV and volatile/inhalational groups. In addition, there is a considerable relationship between IV anesthesia and poorer recurrence-free survival (P = 0.015), but there was no considerable difference in 5-year overall survival (P = 0.307) between the IV group and the volatile/inhalational group. It should be noted that an Exp (B) greater than 1 indicated an increased risk of recurrence and less than 1 the reverse.
According to the previous studies, intravenous and inhalational anesthetic drugs may affect the nature of cancer and host immunity not only by triggering cellular receptors and cell signaling pathways, but also by affecting gene transcription . They can also accelerate the progression of cancer metastasis by suppressing several immune systems, such as NK cells, which are known to prevent cancer cell dissemination [6, 8, 15]. Several studies have demonstrated that inhalational anesthetics drugs, including sevoflurane, may accelerate cancer cell spread through up-regulation of hypoxia-inducible factor (HIF) and immunosuppression by harming the natural killer (NK) cell function. In addition, several studies have indicated that propofol may decrease the expression of HIF-1α and prevent tumor growth [3, 16]. Furthermore, Sevoflurane may decrease the function of cell-mediated immunity (CMI) and trigger the apoptosis of T lymphocytes, which leads to increased tumor growth, metastasis and invasion of tumor cells. Contrarily, propofol showed anti-tumor impacts by triggering the differentiation and activation of T helper lymphocytes . Therefore, sevoflurane has a proinflammatory effect and may accelerate the proliferation and metastasis of cancer cells following the breast cancer operation. In addition, anesthetic management with propofol has an anti-inflammatory and antioxidative effect and may decrease the surgery-associated cytokine production and inhibit immunosuppression [3, 18]. In a bid to identify the optimal anesthetics option in patients with breast cancer, the current study was designed to assess the overall survival and disease-free survival after surgery in breast cancer patients receiving propofol or isoflurane during the operation. We demonstrated that patients receiving isoflurane (volatile/inhalational group) had a longer recurrence-free survival (P = 0.039) than those receiving propofol (IV group). Nevertheless, the overall survival was not considerably different between these two groups. Currently, there are controversial data considering the optimum anesthesia for patients with cancer. Similar to our findings, Yoo and colleagues  in a retrospective study on more than five thousand patients with breast cancer observed no considerable association between the type of anesthesia and recurrence-free or overall survival . In addition, several other studies also reported similar results. However, Wigmore et al.  demonstrated that the mortality rate of the inhaled anesthesia patients was statistically higher than those of the intravenous anesthesia group (P-value < 0.001, HR = 1.47).
Considering the recurrence-free survival, Yoo et al.  observed that disease-free survival was not considerably varied between groups of intravenous anesthesia and inhalation anesthesia, which was inconsistent with our findings. However, in agreement with our study, Kim et al.  indicated that in patients with breast cancer, intravenous anesthesia was not associated with disease-free survival compared to inhalation anesthesia (P-value = 0.763) .
Furthermore, Kyu Oh and colleagues  in a retrospective cohort study on 1538 patients with gastric cancer, demonstrated that there is no considerable difference in 1-year survival considering the type of received anesthesia . Nevertheless, Wigmore et al. , in a retrospective study on more than seven thousand cancer patients indicated that patients receiving volatile anesthesia had a considerably higher mortality rate during the 3-year follow-up . In addition, another conducted retrospective study on more than one thousand patients with colon cancer observed that propofol-administered patients had better survival in comparison with desflurane-treated patients .
Studies indicated that administration of regional anesthesia impacts the immune and inflammatory response of the patient. In this regard, it is assumed that local anesthesia may lead to better outcomes patients with breast cancer [22, 23]. Nevertheless, in the present study patients receiving local anesthesia and paravertebral blocks were excluded.
In addition to the anesthesia method, administration of analgesics may impact the prognosis of breast cancer. Furthermore, a study on 1143 patients with breast cancer indicated that intraoperative administration of opioids improves the recurrence-free survival in patients with triple-negative breast cancer (TNBC) .
One of the main strengths of our study is assessing the tumor characteristics such as size, tumor grade, stage, and receptors. In addition, there are several limitations regarding the present study including the small population size, and the single-center, retrospective study design and residual confounding by unmeasured or unknown covariates. Another limitation to our study is the impacts of opium, which is routinely administered pre- and post-operatively in patients with breast cancer. In this regard, in the present study all the patients in both group received opioids for pain relieving. In conclusion, the present study indicated that the overall survival was not considerably different in patients receiving volatile and IV anesthesia. In this regard, further clinical trials are required to identify the optimum anesthesia for patients undergoing cancer surgeries.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. We can provide the sources and the data used in the study can be deposited publically.
Hovaguimian F, Braun J, Z’Graggen BR, Schlapfer M, Dumrese C, Ewald C, et al. Anesthesia and circulating tumor cells in primary breast cancer patients: a randomized controlled trial. Anesthesiology. 2020;133(3):548–58.
Sessler DI, Pei L, Huang Y, Fleischmann E, Marhofer P, Kurz A, et al. Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial. The Lancet. 2019;394(10211):1807–15.
Shiono S, Shibata SC, Kabata D, Shintani A, Ikeda T, Fujino Y. Comparison of 1-year recurrence-free survival between sevoflurane and propofol use for general anesthesia management in primary breast cancer surgery. J Anesth. 2020;34(5):694–701.
Oh CS, Lee J, Yoon TG, Seo EH, Park HJ, Piao L, et al. Effect of equipotent doses of propofol versus sevoflurane anesthesia on regulatory T cells after breast cancer surgery. Anesthesiology. 2018;129(5):921–31.
Galos EV, Tat TF, Popa R, Efrimescu CI, Finnerty D, Buggy DJ, et al. Neutrophil extracellular trapping and angiogenesis biomarkers after intravenous or inhalation anaesthesia with or without intravenous lidocaine for breast cancer surgery: a prospective, randomised trial. Br J Anaesth. 2020;125(5):712–21.
Lee JH, Kang SH, Kim Y, Kim HA, Kim BS. Effects of propofol-based total intravenous anesthesia on recurrence and overall survival in patients after modified radical mastectomy: a retrospective study. Korean J Anesthesiol. 2016;69(2):126–32.
Hooijmans CR, Geessink FJ, Ritskes-Hoitinga M, Scheffer GJ. A systematic review of the modifying effect of anaesthetic drugs on metastasis in animal models for cancer. PLoS ONE. 2016;11(5):e0156152.
Yoo S, Lee HB, Han W, Noh DY, Park SK, Kim WH, et al. Total intravenous anesthesia versus inhalation anesthesia for breast cancer surgery: a retrospective cohort study. Anesthesiology. 2019;130(1):31–40.
Tsuchiya Y, Sawada S, Yoshioka I, Ohashi Y, Matsuo M, Harimaya Y, et al. Increased surgical stress promotes tumor metastasis. Surgery. 2003;133(5):547–55.
Fodale V, D’Arrigo MG, Triolo S, Mondello S, La Torre D. Anesthetic techniques and cancer recurrence after surgery. Sci World J. 2014;2014:328513.
Forget P, Vandenhende J, Berliere M, Machiels JP, Nussbaum B, Legrand C, et al. Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis Anesth Analg. 2010;110(6):1630–5.
Wigmore TJ, Mohammed K, Jhanji S. Long-term survival for patients undergoing volatile versus IV anesthesia for cancer surgery: a retrospective analysis. Anesthesiology. 2016;124(1):69–79.
Foroutan M, Rostami A, Majidiani H, Riahi SM, Khazaei S, Badri M, et al. A systematic review and meta-analysis of the prevalence of toxoplasmosis in hemodialysis patients in Iran. Epidemiol Health. 2018;40:e2018016-e.
Yap A, Lopez-Olivo MA, Dubowitz J, Hiller J, Riedel B, Global Onco-Anesthesia Research Collaboration G. Anesthetic technique and cancer outcomes: a meta-analysis of total intravenous versus volatile anesthesia. Can J Anaesth. 2019;66(5):546–61.
Weng M, Chen W, Hou W, Li L, Ding M, Miao C. The effect of neuraxial anesthesia on cancer recurrence and survival after cancer surgery: an updated meta-analysis. Oncotarget. 2016;7(12):15262.
Hong B, Lee S, Kim Y, Lee M, Youn AM, Rhim H, et al. Anesthetics and long-term survival after cancer surgery-total intravenous versus volatile anesthesia: a retrospective study. BMC Anesthesiol. 2019;19(1):233.
Yan T, Zhang GH, Wang BN, Sun L, Zheng H. Effects of propofol/remifentanil-based total intravenous anesthesia versus sevoflurane-based inhalational anesthesia on the release of VEGF-C and TGF-beta and prognosis after breast cancer surgery: a prospective, randomized and controlled study. BMC Anesthesiol. 2018;18(1):131.
Jiang S, Liu Y, Huang L, Zhang F, Kang R. Effects of propofol on cancer development and chemotherapy: potential mechanisms. Eur J Pharmacol. 2018;831:46–51.
Kim MH, Kim DW, Kim JH, Lee KY, Park S, Yoo YC. Does the type of anesthesia really affect the recurrence-free survival after breast cancer surgery? Oncotarget. 2017;8(52):90477.
Oh TK, Kim HH, Jeon YT. Retrospective analysis of 1-year mortality after gastric cancer surgery: total intravenous anesthesia versus volatile anesthesia. Acta Anaesthesiol Scand. 2019;63(9):1169–77.
Wu Z-F, Lee M-S, Wong C-S, Lu C-H, Huang Y-S, Lin K-T, et al. Propofol-based total intravenous anesthesia is associated with better survival than desflurane anesthesia in colon cancer surgery. Anesthesiology. 2018;129(5):932–41.
Pérez-González O, Cuéllar-Guzmán LF, Soliz J, Cata JP. Impact of regional anesthesia on recurrence, metastasis, and immune response in breast cancer surgery: a systematic review of the literature. Reg Anesth Pain Med. 2017;42(6):751–6.
Finn DM, Ilfeld BM, Unkart JT, Madison SJ, Suresh PJ, Sandhu NPS, et al. Post-mastectomy cancer recurrence with and without a continuous paravertebral block in the immediate postoperative period: a prospective multi-year follow-up pilot study of a randomized, triple-masked, placebo-controlled investigation. J Anesth. 2017;31(3):374–9.
Montagna G, Gupta HV, Hannum M, Tan KS, Lee J, Scarpa JR, et al. Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer. Br J Anaesth. 2021;126(2):367–76.
The authors would like to thank Shiraz University of Medical Sciences, Shiraz, Iran and Dr. Vahid Zangouri, Dr. Majid Akrami and Dr. Masoume Ghodousi.
Ethical approval and consent to participate
The research performed under the Declaration of Helsinki. The ethics committee of Shiraz University of Medical Sciences approved the study protocol. The ethics committee reference number was IR.SUMS.MED.REC.1399.307. (https://ethics.research.ac.ir/EthicsProposalView.php?id=150323). Informed consent was obtained from all study participants.
Consent for publication
The written informed consent for publication was obtained.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Karami, M.Y., Dehghanpisheh, L., Karami, A. et al. Comparison of volatile/inhalational and IV anesthesia in long-term survival of patients with breast cancer: a retrospective study. Eur J Med Res 27, 271 (2022). https://doi.org/10.1186/s40001-022-00911-9