The Effect of Surgical Intervention of Endometriosis to CA-125 and Pain

Endometriosis is an inflammatory condition characterised by the presence of endometrial growth beyond the uterine cavity. It is a debilitating disease requiring multiple modalities of treatment. In considering surgery as the option of treatment, the benefits should outweigh the risk. Besides direct surgical risk, intervention may lead to a reduction of ovarian reserve, in addition to premature menopause and low fecundity. To date, there is an inconclusive evidence to support any specific parameters in monitoring disease progression following surgical intervention. Serum cancer antigen (CA)-125 is expressed by coelomic epithelium and has been extensively studied as a biomarker for endometriosis. Elevated expression of CA-125 has been shown in endometrial tissues and the marker increased indirectly from peritoneal irritation that accompanies an extensive form of endometriosis. Additionally, the visual analogue scale (VAS) scores have been used as an objective measurement for measuring pain, especially in a complex disease such as endometriosis. This review aims to consolidate a series of clinical trials that utilised CA-125 level and VAS score as tools for monitoring patients undergoing surgery for endometriosis.


Introduction
Endometriosis is a benign condition characterised by the presence of endometrial cells in the extrauterine cavity, which potentiates chronic inflammation. It commonly involves peritoneum and pelvic organs, with extraabdominal locations are also being reported (1). The disease can be asymptomatic and could be discovered accidentally during laparoscopic surgery. The most typical symptoms include chronic pelvic pain that could last for 6 months or longer, dysmenorrhea and dyspareunia, which is pain occurring during coitus. Numerous theories have been proposed for the pathogenesis of endometriosis, such as retrograde menstruation, immunological response and progesterone resistance, with the presence of underlying perturbation of progesterone receptor isoforms ratio (2). Medical treatment has been shown to have varying success (3), while surgical treatment carries operative risk and may impair future fecundity.
The gold standard for diagnosis of endometriosis is by visual inspection, preferably by histological confirmation, thus requiring surgery with its added risks. The use of molecular regarding endometriosis surgery in relation to VAS returned with a total of 324 articles with 43 from Scopus and 281 from MEDLINE. A total of 12 duplicates were removed. Review articles, case reports and literature from books were then excluded. A total of nine articles met the inclusion criteria and were deemed relevant to our objective. The full manuscripts were obtained for further review.

The Effects of Surgery for Endometriosis on Serum CA-125 Level
CA-125, which is the glycoprotein expressed by coelomic epithelium, is an extensively studied marker. The previous study had shown that elevated levels of pre-operative serum CA-125 were recorded in patients with moderate to severe endometriosis compared to control (4).
Furthermore, immunocytochemical studies indicated that CA-125 is present in the endometriotic lesion. The elevation observed in serum CA-125 and its presence in endometriotic lesions led to investigations as a diagnostic tool. However, the pathogenesis of endometriosis itself is still unclear; hence it is not surprising that a recent meta-analysis has shown that CA-125 is not useful for diagnostic purposes (5).
There are two postulations on how endometriosis causes a rise in the serum CA-125 level. The first is a higher concentration of antigen at the cell-surface levels in endometriotic lesions compared with normal endometrium. Secondly, it is caused by the inflammation that commonly accompanies endometriotic lesion (4). A subsequent study showed that endometriosis is not a source of elevated CA-125 level, but rather the peritoneal irritation that frequently accompanies extensive forms of the disease could have a significant role in causing the perturbation (6). On this basis, serum CA-125 may be used for monitoring the degree of peritoneal irritation due to endometriosis. Nonetheless, the CA-125 role in monitoring the disease has not been established.
Seven articles were included in the final review, as summarised in Table 1.
None of the articles found by a search in the two databases had a primary objective of comparison between the pre-and post-operative serum CA-125 levels in an endometriosis cohort. During an initial exploration of a search engine, a study was found to specifically look at the effects biomarkers as a diagnostic tool in endometriosis remains inconclusive, albeit those biomarkers' role in prognostication of the disease has so far never been clinically validated and broadly utilised. Hence, this review aims to consolidate evidence of the usefulness of cancer antigen (CA)-125 levels and pain score using visual analogue scale (VAS) at pre-and post-surgery for endometriosis, as the major predictive outcome.

Methods
This review was performed as part of our molecular research on the correlation of serum CA-125 and pain scores on progesterone receptor isoform perturbations in patients with endometriosis, which was approved by our institutional ethical committee (FFF-2017-045). The available evidence for serum CA-125 and VAS scores concerning endometriosis surgery was reviewed. A literature search was performed using two databases, using MEDLINE on OVID and Scopus. The terms 'Endometriosis' and 'CA125' and 'surg*/operati*' were used for presence in the title, abstracts and keywords. Limits were set to the last three decades from 1990 to March 2020. A similar search was repeated with the term 'visual analogue scale/ VAS' replacing 'CA125'. Original studies of clinical trials of surgery on endometriosis patients involving the measurements of serum CA-125 and VAS were selected and reviewed. Relevant clinical papers that were cited in these articles were also scrutinised to ensure earlier critical information was not omitted. Related literature concerning the subjects was also analysed for completeness.

Results
A total of 429 potentially relevant articles were retrieved from the search regarding endometriosis surgery in relation to CA-125 with 176 from the Scopus and 253 from MEDLINE. A total of 13 duplicates were then removed. Review articles, case reports and literature from books were excluded. A total of six articles were deemed relevant to our objective. Full-text articles were obtained for five, with only an English abstract was available for an original article published in China. An article was added from our preliminary search of the topic, which made it a total of seven articles were reviewed. A similar search for literature Review Article | Monitoring endometriosis using VAS and CA-125 Notes: ELISA = Enzyme-linked immunosorbent assay; *Only English abstract available after 4 weeks, but no values were available due to information available was only from an English abstract. Therefore, all evidence points towards the improvement of serum CA-125 up to 12 weeks after the surgery for endometriosis. Although it has been shown by Cochrane metaanalysis (5) that serum CA-125 is not useful as a diagnostic tool for endometriosis, there is a potential use if monitoring is required after surgical intervention.
Overall the articles reviewed here varied in quality. The main problem was the lack of studies comparing pre-and post-surgery as the primary outcome. All studies had pre-surgery serum CA-125 levels, but only three out of seven had post-surgery levels for comparison. Of the seven studies, only three had a control group, yet there were variations in the methods measuring CA-125 amongst the studies.

The Effects of Surgery for Endometriosis on Pain
One of the main symptoms of endometriosis is pain. A systematic review (14) found that VAS is the most frequently used scale, which can provide both clinicians and researchers with tools to evaluate treatment response for endometriosis-related pain. Improvement in the pain score may reflect the surgical disruption of the neurogenic inflammation, hyperalgesia and dysreflexia of various pelvic viscera (15). Nine studies were included in our final analysis.
It is difficult to compare the VAS scores as the studies reviewed in the literature reported using both mean and median scores. Furthermore, the type of VAS used varied. Seven of the studies described using a 10-point VAS for measurement (16)(17)(18)(19)(20)(21)(22). Another two used a 10 cm linear scale (23) and an 11-point scale (24), respectively. To compound matters, the classification of pain also varies from just pelvic pain in two studies (17,23) to a breakdown of the type of pain, which were dysmenorrhea, dyspareunia and non-menstrual pelvic pain or chronic pelvic pain in five studies (16,(18)(19)(20)24). The use of just pelvic pain, which was inclusive of all parameters, would have been more advantageous as the patients may not have resume or cease having coitus or menstruation during follow-up.
The time points when the VAS scores were documented post-surgery also varied between studies from 1 month up to 60 months. There were three studies (18,19,23), which recorded VAS scores at 3 months. Out of those, only of surgery on endometriosis patients on serum CA-125. The study by Kokeb et al. (7) was a crosssectional study conducted in an Asian population of a third world country. A total of 100 patients with endometriosis were included; however, the stages of the disease were not mentioned. The authors found that there was a highly significant drop of mean serum CA-125 level from pre-to post-operation (60.5 IU/mL to 27.5 IU/mL). Unfortunately, there was neither a control group nor mention of the actual time point for postsurgery when the levels were taken. Despite the shortcomings of the study, it was the only study that specifically investigated the effects of surgery for endometriosis on serum CA-125 level.
All seven studies had pre-surgery serum CA-125 levels. The levels varied between studies with two studies showing normal levels (8,9) and five publications showing elevated levels (7, 10-13). Yet, comparison to a control group was only available in three studies. Nevertheless, only one study (8) performed an analysis comparing the control and endometriosis groups during pre-surgery, which did not show any statistical significance. This, however, was in an asymptomatic cohort of endometriosis patients. The other two studies, which had a control group, did not elaborate on statistical analysis for differences (9,11). Thus, the evidence suggested that pre-surgery levels in patients with endometriosis varied. In the minimal to a mild stage of the disease, the levels for CA-125 were similar to controls.
Only three studies had post-surgery levels of serum CA-125 (7,10,11). However, the time of measurement of post-operative values varied from 24 h to 6 months. The differences in the time points could explain the elevated levels of serum CA-125 as observed in Ruan et al. (10), which measured at earlier time point but normal levels are reported by Kokeb et al. (7), which measured serum CA-125 level after several weeks of operation.
Only the three studies mentioned above had measured pre-and post-surgery levels in their endometriosis cohort (7,10,11). All three showed reductions in the serum CA-125 levels after surgery. Ruan  surgeries, with three studies reported significant reduction (16,20,24).

Conclusion
The myriad of pathways in the pathogenesis of endometriosis makes the diagnosis and monitoring of disease difficult. Surgery is one of the options of treatment for endometriosis, and a method to monitor the benefit of this modality is much sought after. Serum CA-125 has been shown to be non-beneficial as a tool for diagnosis. However, several studies have suggested the role of monitoring as similar patterns of improvement were observed in the serum CA-125 levels after surgery. Further studies with the primary outcome of improvement in serum CA-125 levels after surgery and reduced variables are necessary for confirmation. In addition to CA-125, studies have shown improvement in VAS scores after surgery and the improvement became significant after 3 months as pain is one of the main symptoms associated with endometriosis. Despite risk due to the surgery itself, endometriosis surgery should be recommended for the improvement of pain and serum CA-125 should be considered as a monitoring tool post-surgery.

Conflict of Interest
We wish to confirm that there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome.

Funds
Funding from our centre; and FRGS/1/ 2017/SKK08/UKM/01/4. Sutton et al. (23) measured pelvic pain VAS score using a median score, which showed a nonstatistically significant improvement. A possible reason that the result did not reach significance was the fact that 90% of their cohort was in stage I-II. The other two studies also showed improvement in dysmenorrhea, dyspareunia and pelvic pain; however, no statistical analysis for the difference was published. On the other hand, four studies showed a statistically significant drop in pain score (16,20,21,24). These studies had taken their VAS scores between 6 to 60 months. Most of these studies agreed that there was significant pain improvement achieved at 6 months post-surgery.
All of the nine studies included in this review used the revised American Society of Reproductive Medicine (rASRM) staging for endometriosis (25). In terms of the cohort of endometriosis patients, those with a majority of patients in stage I-II (16,19,20,23) and those with a majority in stage III-IV (17,24), all showed a reduction in VAS scores. However, only four studies (16,19,20,23) showed a significant reduction. Although the evidence showed a marginal and inconsistent association between endometriosis stage and the severity of pelvic symptoms (26), the studies reviewed suggest that pain improvement was noted regardless of the stage of the disease.
The studies in our review did not have any direct comparison between laparoscopic and open surgery in improving VAS scores. The majority of the studies in this review used a laparoscopic approach for surgery. The laparoscopic approach is, however, advisable as the previous meta-analysis has shown it to be effective. Evidence from Cochrane meta-analysis (27) suggests that laparoscopic surgery compared to diagnostic laparoscopy alone reduces pain associated with endometriosis in all stages of the disease. The summary of the clinical studies reviewed for the effects of endometriosis surgery on VAS scores is shown in Table 2.
There is a challenge in interpreting these studies due to the non-homogeneity of the methods. These include the design, type of surgery, post-surgery time points of VAS scores, method of reporting results and the description of pain. A positive note was that six out of the nine studies were reasonably recent, less than 10 years (16)(17)(18)(19)(20)22). However, all studies were in agreement that there is an improvement in either the mean or median of the VAS scores after the