Research
HJOG 2024, 23 (3), 218-224| doi: 10.33574/hjog.0568
Vasilios Pergialiotis1, Dimitrios Efthymios Vlachos1, Loukas Feroussis1, Vasilios Lygizos1, Ioannis Rodolakis1, Konstantinos Bramis2, Eleftherios Zachariou1, Georgios Daskalakis1, Nikolaos Thomakos1, Dimitrios Haidopoulos1
1First Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, “Alexandra” General Hospital, Athens, Greece
22nd Department of Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Correspondence: Vasilios Pergialiotis, MD, MSc, PhD, 6 Danaidon str. Halandri 15232 – Greece, e-mail: pergialiotis@yahoo.com
Abstract
Background: Splenectomy is a very common procedure that is frequently necessary in cases requiring upper abdominal surgery for ovarian cancer. To date, the impact of postoperative thrombocytosis on ovarian cancer survival has not been studied. In the present retrospective cohort study we chose to evaluate the impact of post-splenectomy thrombocytosis on survival outcomes of patients with advanced epithelial ovarian cancer that were submitted to maximal effort cytoreductive procedures.
Methods: We conducted a retrospective cohort study based on cases that had major debulking procedures, involving upper abdominal surgery for epithelial ovarian cancer.
Results: Overall, 82 women had splenectomy of whom, 52 (63%) developed thrombocytosis. The results of the univariate analysis revealed that postoperative thrombocytosis did not increase the risk of disease recurrence (62.94 months (31.71, 93.27) vs 31.40 months (21.39, 41.41) log-rank=.683). Similar results were obtained for overall survival of included patients which was comparable among the two groups (87.50 months (53.47, 121.52) vs 47.78 months (34.30, 61.25), log-rank=.511). Logistic regression analysis revealed that only age was a predictive factor of postoperative thrombocytosis with an effect of minimal clinical importance (OR 0.94, 95% CI 0.89, 1.00).
Conclusion: Post-splenectomy thrombocytosis does not affect the survival outcomes of patients with advanced epithelial ovarian cancer that undergo major debulking procedures. This might be explained by the underlying mechanisms which in the case of postoperative thrombocytosis seem to be completely disconnected from the pathophysiology of cancer.
Key words: Vaginal birth, cesarean section, VBAC, trial of labor, TOLAC, obstetricians, attitude
Introduction
With an estimated lifetime risk of 1 in 78 women and a lifetime risk of disease-specific death of 1 in 108 women, ovarian cancer is the third most frequent gynecologic malignancy encountered globally1. The risk of ovarian cancer is influenced by several major risk factors, such as advanced age, past radiation exposure, nulliparity, genetic mutations, obesity, and family history2. Since there are currently no established screening methods, it is uncommon for the disease to be discovered early. As a result, most cases are referred for diagnosis when the tumor load causes symptoms like dyspepsia, bloating, and abdominal pain.
The prevalence and histological patterns of ovarian cancer vary around the world, but because the disease typically manifests at an advanced stage, it is regarded as systemic in most cases. As a result, chemotherapy, which primarily consists of a combination of platinum (carboplatin) and taxane (paclitaxel) chemotherapy, is the main treatment for ovarian cancer3. When combined with anti-VEGF (vascular endothelial growth factor) therapy, the use of PARP (poly-ADP ribose polymerase) inhibitors has significantly extended overall and recurrence-free survival in certain populations with known mutations in the BRCA 1 and BRCA 2 genes and those with homologous recombination deficiency3. Platinum resistant disease is considered an ominous sign according to the findings of several studies4,5.
Despite advances in the medical treatment of the disease surgical intervention remains essential because complete tumor debulking increases the patients’ survival rates considerably. Since most of the evidence is still inconclusive and stems from studies with methodological flaws in terms of the population included and procedure completion adequacy, it is still unclear whether primary debulking surgery improves survival over interval debulking6-8.
In light of this data, medical professionals endeavored to broaden the scope of surgical operations, which progressively became more intricate as gynecologic oncologists acquired greater expertise and were able to execute multiorgan excisions and upper abdominal surgeries. Despite its impact on patients` perioperative morbidity, maximal effort cytoreductive treatments significantly improve survival for patients with ovarian cancer and appear to be linked with acceptable morbidity that does not necessarily exclude the use of adjuvant chemotherapy9,10. These days, splenectomy is a very common operation for upper abdominal surgery for ovarian cancer since patients with advanced stage disease who undergo primary debulking surgery typically develop hepatic and surface metastases10-12.
Splenectomy significantly affects the number of postoperative platelets, resulting in postoperative thrombocytosis. The impact of pretreatment thrombocytosis has been reviewed by several researchers and in a recent meta-analysis we designated that it significantly affects ovarian cancer survival. The actual underlying pathophysiology has not been elucidated fully; however, it seems that the release of pro-inflammatory and inflammatory factors from the disease itself results in a cascade that promotes cancer progression. Paraneoplastic thrombocytosis seems to be a component of this vicious circle as it is associated with the secretion of these markers.
To date, the impact of postoperative thrombocytosis on ovarian cancer survival has not been studied. We speculated that its occurrence might affect patients` survival rates, despite the fact that it cannot be considered a paraneoplastic phenomenon, given that a known predisposing factor is present. In the present retrospective cohort study we chose to evaluate the impact of post-splenectomy thrombocytosis on survival outcomes of patients with advanced epithelial ovarian cancer that were submitted to maximal effort cytoreductive procedures.
Methods
The methodological design of this study has been previously presented. Briefly the present cohort is based on a consecutive series of patients that were surgically treated for advanced epithelial ovarian cancer between January 2016 and December 2021. Based on the patient’s performance status and tumor load, either interval debulking surgery (IDS) or primary debulking surgery (PDS) was chosen. Factors that prohibited patients per se from undergoing surgery included the existence of extra-abdominal metastases or substantial liver parenchymal disease that required hepatic excision beyond the scope of sphenoid resection. The study was designed in accordance with the declaration of Helsinki for medical research involving human subjects and the institutional review board of our hospital approved this study prior to its onset (IRB approval number: 781/21).
Definitions
The surgical complexity of the procedures was evaluated with the Mayo Clinic (Aletti) score that assigns points of surgical complexity according to the number of excised organs and extent of tumor debulking. The summarized score is categorized as low complexity when ≤3 points are assigned, intermediate complexity when 4-7 points are assigned and high complexity in the presence of >7 points.
Survival outcomes were recorded from the onset of diagnosis until clinical or radiology findings of disease relapse (for recurrence free survival) and until patient death (for overall survival) respectively. Patient records were used to record disease relapse and/or death for cases that had been clinically reviewed during the last 30 days; for the remaining patients, information on survival was obtained through direct phone calls.
The presence of postoperative thrombocytosis was documented within a timeframe of 30 days from the surgical procedure and the highest platelet value was obtained from the complete blood count (CBC) test. In the literature several cut-off points have been described for pre-treatment thrombocytosis. In the present study we determined that an optimal cut-off of 350.000/ml would best describe the occurrence of postoperative thrombocytosis, given the actual distribution of platelets following a splenectomy.
Statistical analysis
Statistical analysis was performed using the SPSS 20.0 program (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Evaluation of the normality of distributions was performed with graphical methods and the Kolmogorov-Smirnoff analysis. The differences of continuous variables were assessed using the Mann-Whitney and Kruskal-Wallis test (due to the abnormal distribution that was observed during the evaluation of normality) whereas dichotomous variables were analyzed with the chi-square test. Fisher’s exact test was applied wherever the number of observations was lower than five in the case of dichotomous variables. The Kaplan-Meier method was carried out to perform survival-analyses. The level of significance for all analyses was set to p<.05.
Results
We were able to identify 245 that had maximal effort debulking procedure for epithelial ovarian cancer. Of those, 22 were excluded due to absence of relevant data. Overall, 82 women had splenectomy of whom, 52 (63%) developed thrombocytosis. The characteristics of included patients are depicted in Table 1. Of those, 44 women developed disease recurrence, and 31 women ultimately died from the disease.
The results of the univariate analysis revealed that postoperative thrombocytosis did not increase the risk of disease recurrence (62.94 months (31.71, 93.27) vs 31.40 months (21.39, 41.41) log-rank=.683) (Figure 1). Similar results were obtained for overall survival of included patients which was comparable among the two groups (87.50 months (53.47, 121.52) vs 47.78 months (34.30, 61.25), log-rank=.511) (Figure 1).
Figure 1. Kaplan‑Meier curves for recurrence free survival and overall survival outcomes.
Multivariate analysis indicated that thrombocytosis had an effect on the overall survival of patients which, however, did not reach the level of statistical significance (p=.064) (Table 2). Of all the remaining factors that were selected in the predictive model for recurrence free and overall survival, only the setting of the operation had a significant effect which was mainly seen in recurrence free survival, whereas the overall survival was close to the level of statistical significance.
Logistic regression analysis revealed that only age was a predictive factor of postoperative thrombocytosis with an effect of minimal clinical importance (OR 0.94, 95% CI 0.89, 1.00).
Discussion
The findings of our study suggest that post-splenectomy thrombocytosis does not affect the progression free survival nor the overall survival of patients. This result is in partial contrast to that of our previous meta-analysis which indicated that pretreatment thrombocytosis is an essential factor that directly affects patients` survival rates13.
Researchers have found previously that the release of cytokines in patients with ovarian cancer causes thrombopoiesis, which is why paraneoplastic thrombocytosis manifests as a component of the inflammatory process that accompanies14. This observation explains why pre-treatment thrombocytosis might affect patients` survival as it indicates that it is a part of a vicious circle that repeatedly results in excretion of inflammatory factors that consequently increase the number of thrombocytes. This explains why some studies revealed that patients with significant reduction in platelet number post-chemotherapy had increased survival rates15-16.
Post-splenectomy thrombocytosis is considered reactive and is considered the result of the operation, including the inflammatory process that accompanies it. In most cases it becomes evident within the first month from the operation and persists for an unpredictable and greatly variable period of time17,18. Considering this it does not seem to being directly related to the actual tumor load and the process that accompanies it, therefore, partially explaining why it does not predispose to worse survival outcomes. The actual reasons of postoperative thrombocytosis have not been completely elucidated. It is believe that patients undergoing splenectomy for non-traumatic diseases are more prone to develop thrombocytosis when preoperative platelet counts are increased within the normal limits and that men are more prone to develop the condition compared to women 19. In our series, none of the factors that were considered as potential contributors, considering the burden of the disease, patients` age and smoking status were either predictive or clinically meaningful, indicating the difficulty to detect patients at risk.
Strengths and limitations of our study
Our study is based on one of the largest cohorts of patients that is derived from a single institution that is accredited by ESGO as a center of excellence for the management of patients with ovarian cancer. In the present series we indicated for the first time in the international literature the lack of an association between postoperative (post-splenectomy) thrombocytosis and ovarian cancer survival.
On the other hand, despite the use of a continuous series of patients, the retrospective design of our study cannot completely preclude the possibility of bias, including selection and confounding bias. Moreover, the retrospective nature of the study, precluded the investigation of the specific cause of death of included patients; therefore, the actual cancer specific survival remains unknown, as well as the actual proportion of patients that actual return to normal platelet counts and the interval until this phenomenon occurs.
Conclusion
Post-splenectomy thrombocytosis does not affect the survival outcomes of patients with advanced epithelial ovarian cancer that undergo major debulking procedures. This might be explained by the underlying mechanisms which in the case of postoperative thrombocytosis seem to be completely disconnected from the pathophysiology of cancer.
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