In this study, we investigated the prognostic impact of three intraoperative variables indicating hemodynamic instability: cumulative duration of MAP <65 mmHg, MDPE, and wobble, on survival outcomes in patients with HGSOC who underwent CRS. The results identified a MAP under 65 mmHg for ≥30 min, MDPE <−4.0%, and wobble ≥7.5% as poor prognostic factors for PFS. In contrast, these factors did not affect patients’ OS.
HGSOC is one of the few epithelial cancers, in which the removal of metastatic tumors has been found to improve survival outcomes [5, 6]. In reality, despite the best efforts by gynecologic oncologists to achieve complete cytoreduction, patients with HGSOC experience recurrence several times, develop chemoresistance, and succumb to the disease. Therefore, it is very important to discover novel prognostic factors in these patients. Based on our study results, if patients have even one of the three hemodynamic instability factors, they are identified at high risk of disease recurrence, and physicians may recommend a more aggressive treatment and intensive surveillance with frequent measurements of serum CA-125 levels and imaging studies.
In the current study, we chose the three variables indicating hemodynamic instability for the following reasons: the cumulative duration of MAP <65 mmHg is an absolute, standardized blood pressure indicator. In addition, we considered the MDPE as a comparative, individualized blood pressure indicator. Lastly, wobble was selected as it represented blood pressure instability during surgery. Since these variables have not yet been evaluated in various cancer surgeries in earnest, we have referred to the previous studies conducted in patients with benign diseases [12, 13].
Intraoperative hypotension is common during non-cardiac surgery. According to a sub-study of the POISE-2, a 10,010-patient factorial-randomized trial of aspirin and clonidine for prevention of myocardial infarction, 34.9% of the patients experienced intraoperative hypotension [19]. As intraoperative hypotension is associated with an increase in postoperative mortality and morbidity [8,9,10,11, 20], an expert consensus recommends that intraoperative blood pressure be maintained above 100 mmHg for systolic blood pressure and above 60–70 mmHg for MAP during elective, non-cardiac surgery [7].
Similar to our study, van Waes et al. calculated the cumulative duration of MAP under 60 mmHg during vascular surgery in older patients, and reported that >30 min of MAP under 60 mmHg was significantly associated with myocardial injury (relative risk, 1.7; 98.8% CI, 1.1–2.6; P = 0.004) [10]. Consistent results were also observed when different definitions of hypotension were used (i.e., more than 30 min of ≥30% or ≥40% decrease from baseline MAP) [10]. Meanwhile, a retrospective cohort study by Salmasi et al. also reported that prolonged exposure of MAP under 65 mmHg during non-cardiac surgery increased the odds of both myocardial and kidney injury [9]. These studies highlight the degree and duration of intraoperative hypotension, both of which are important in the development of postoperative complications.
Regarding primary cancer surgery, Huang et al. investigated the impact of intraoperative hypotension on survival outcomes in 676 patients who underwent lung cancer surgery [14]. The authors reported that intraoperative hypotension, defined as a systolic blood pressure <100 mmHg for at least 5 min, was significantly associated with poorer OS (adjusted HR, 1.382; 95% CI, 1.047–1.825; P = 0.023). This study suggested that survival outcomes might be worsened even with a short duration of intraoperative hypotension. In an earlier retrospective study by Younes et al., comprising 116 patients who underwent complete hepatic resection for colorectal metastases, the number of intraoperative hypotension episodes, defined as a ≥ 20% decrease from baseline MAP, was significantly associated with shorter PFS [15]. Despite differences in the study populations and definitions of hypotension in the studies, our study results are consistent with those in previous studies.
Intraoperative hypotension can also be measured by performance measurements, MDPE and wobble, both of which are relatively new indicators for hemodynamic instability. In the previous studies conducted by our research team, MDPE was found to be associated with a 30-day and overall mortality after cardiac surgery performed using cardiopulmonary bypass [12], and wobble was observed to be associated with mortality after liver transplantation [13]. In the current study, we identified additional roles for the performance measurements: MDPE <−4.0% and wobble ≥7.5% were independent poor prognostic factors for PFS in patients with HGSOC, who received CRS. Herein, we propose that both MDPE and wobble are useful biomarkers that can be employed to quantify the degree of intraoperative hypotension and to predict survival outcomes following CRS. While MDPE measures the degree of hypotension, wobble measures blood pressure variability and detects concealed or treated hypotension. Furthermore, the real-time intraoperative measurement of MDPE and wobble is possible, enabling anesthesiologists to provide adequate, timely hemodynamic management by the use of inotropic agents, vigorous fluid resuscitation, or transfusion.
In our study, MAP under 65 mmHg for ≥30 min, MDPE <−4.0%, and wobble ≥7.5%, were associated with deteriorated PFS. The negative value of MDPE indicates a lower intraoperative SBP than the preoperative SBPward, presumably caused by general anesthesia, blood loss, or hypovolemia. Patients with MDPE <−4.0% were more likely to experience MAP under 65 mmHg for ≥30 min (P = 0.001) and to have wobble ≥7.5% (P = 0.015). Therefore, intraoperative hypotension seems to play a major role in increased disease recurrence rate. We hypothesize that hypoxia is responsible for the increased recurrence rate in HGSOC patients who experienced intraoperative hemodynamic instability. Hypoxia is known as a key pro-cancerous feature of the tumor microenvironment. As described by Huang et al. [14], intraoperative hypotension could aggravate a hypoxic tumor microenvironment, inducing the development of aggressive phenotypes of tumors by overexpression of hypoxia-inducible factor-1 (HIF-1) leading to cancer progression and dissemination [21, 22]. Recent evidence also suggests that non-coding RNAs, shuttled via exosomes, regulate cancer biology, and reshape the hypoxic tumor microenvironment [23]. Intraoperative hypotension-induced hypoxia could also promote systemic inflammation, which is known to have pro-tumorigenic effects [24, 25]. Considering the fact that some gene expression and activation of signaling pathways occur in a very short time [26], even a transient exposure to hypoxia during surgery may lead to such changes.
Some might argue that such adverse effects from intraoperative hypotension would not exist in patients who achieved complete cytoreduction as they do not have any gross residual tumor. In the study population, 74.9% achieved complete cytoreduction. However, cancer stem cells within the surgically resected tumor bed might have survived and been affected by intraoperative hypotension-induced hypoxia [27]. The remaining cancer stem cells might have evolved toward drug resistance [28, 29]. Despite adjuvant chemotherapy, resistant cancer stem cells might survive and consequently affect the disease progression in patients [30, 31].
Interestingly, none of the three intraoperative variables for hemodynamic instability affected OS in the current study. The possible explanations for their not affecting OS are as follows: first, the observation period might be relatively short to observe death events. Second, approximately 10% of the relapsed were lost to follow-up within 6 months after the confirmation of the first recurrence. Third, although we did not investigate detailed information on treatment methods for recurrent HGSOC, some might be cured or salvaged by second-line treatment. Fourth, physicians at our institutions have actively enrolled those who recurred to phase III randomized controlled trials, such as GOG-213, DEKSTOP-III, and SOLO2, or other clinical trials, which might affect post-progression survival. Lastly, hypoxic tumor microenvironments induced by intraoperative hypotension might be altered or further evolve during the course of treatments and disease recurrences [32].
Based on the results of our study, we emphasize the clinical importance of monitoring intraoperative blood pressure and preventing hypotension and hemodynamic instability during CRS. The cumulative duration of MAP <65 mmHg, MDPE, and wobble, are potentially modifiable factors. To ensure the probability of cure and improved PFS of patients with HGSOC, intraoperative hemodynamic instability should be avoided and corrected promptly by adequate transfusion or intravenous fluid infusion, and use of drugs, such as vasopressors and inotropes.
The current study has some limitations. First, there might be selection bias or other inherent issues owing to the retrospective study design. Second, although 338 patients were included, a larger sample size may be needed for generalization of the results. Third, while calculating the cumulative duration of MAP <65 mmHg, we did not distinguish patients who developed continuous intraoperative hypotension and those who crossed the threshold repeatedly. Fourth, as survival for ovarian cancer is known to be affected by hospital volume and quality of care [33], inconsistent results might be observed in other study populations. Further large, multi-center cohort studies are warranted to determine more precise cut-off values of the three intraoperative variables for hemodynamic instability and to validate our findings. By combining hemodynamic instability variables, clinical factors, and laboratory test results [34], we might be able to develop models predicting prognosis after primary treatment for clinical utility. Despite these limitations, the current study included selected patients using strict inclusion/exclusion criteria, and investigated the prognostic impact of hemodynamic instability in those with HGSOC for the first time.