Concordance of the scoring algorithms based on serology, imaging and laparoscopy with primary surgical findings and surgical outcome in Epithelial Ovarian Cancer

Concordance of the scoring algorithms based on serology, imaging and laparoscopy with primary surgical findings and surgical outcome in Epithelial Ovarian Cancer

Dr Neethu Puthalon Kunnath *1,   Dr Janmejaya Mohapatra2 , Dr Jagannath Mishra3, Dr Ashok Kumar Padhy4, Dr Suvendu Kumar Mohapatra5, Dr Jita Parija6

 

1.  Dr Neethu Puthalon Kunnath, DGO, MS (O&G), MRCOG, MCh Gynecologic Oncology, Clinical Assistant professor, Department of Gynaecological oncology, AIMS, Kochi.

2. Dr Janmejaya Mohapatra, MD (O&G), Associate Professor, Department of Gynaecological oncology.

3. Dr Jagannath Mishra, MS (O&G) MCh Gynecologic Oncology, Consultant,Department of Gynaecological oncology. TMC Kolkata.

4. Dr Ashok Kumar Padhy, MD(O&G), Assistant Professor, Department of Gynaecological Oncology.

5. Dr Suvendu Kumar Mohapatra MD (Radiodiagnosis), Department of Onco-Radiology.

6. Dr Jita Parija, MD (O&G), Professor, Department of Gynaecological oncology.

Department(s) and institution(s) – Department of Gynaecological Oncology and Department of Onco-Radiology, Acharya Harihar Post Graduate Institute of Cancer, Cuttack, Odisha, India. PIN 753007.

 

*Correspondence to: Dr Neethu Puthalon Kunnath, DGO, MS (O&G), MRCOG, MCh Gynecologic Oncology, Department of Gynecological oncology, Acharya Harihar Post Graduate Institute of Cancer, Cuttack, Odisha, India.

 

Copyright.

© 2024 Dr Neethu Puthalon Kunnath. This is an open access article distributed under the Creative Commons Attribution   License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 15 April 2024

Published: 26 April 2024

DOI: https://doi.org/10.5281/zenodo.11105386


Abstract

There is little doubt that the use of radical surgery for patients with carcinomatosis in which complete resection can be obtained will have a positive impact on survival in ovarian cancer. The benefit has to be above the morbidity and mortality of such operations to the patient. Selection of patients is performed using clinical and serologic criteria, imaging, laparoscopy and surgeon’s opinion (tumour board decisions).

Aim of the study is to predict the outcome of cytoreductive surgery and the role of use of serologic markers such as CA-125, imaging modalities such as computed tomography (CT) and laparoscopy-based scores in the management of epithelial ovarian cancer in low resource settings.

In this study, both the groups, the one with complete cytoreduction (CC=0) and the other with incomplete cytoreduction (CC≠0) were comparable in terms of age, parity and menopausal status. The median CA 125 levels in both the groups were not found to be statistically different. On multiple regression analysis CT score did not contribute independently to the prediction of completeness of cytoreduction.

The surgical scoring models, Fagotti scoring, Open scoring, PCI scoring, Aletti surgical complexity scoring were individually compared in the CC0 and CC≠0 group. In the Multiple regression analysis, considering Age, CT Score, Fagotti Score, Open Score, PCI and SCS as independent variables, Fagotti score and SCS emerged as the independent predictors of Complete cytoreduction status. The model explained 58.53 percentage of the variance in the outcome variable with major predictor of the complete cytoreduction status as Fagotti score. A value > 5 of fagotti score showed higher likelihood for CC≠0. As for open score, a value > 5 showed higher likelihood for CC≠0. SCS couldn’t be assessed independently because of the small sample size, which fails to bring out the essential contribution of SCS to CC 0.

Key words: Cytoreduction Surgical Procedures, Peritoneal Neoplasms, Ovarian Epithelial Carcinoma, Ovarian Neoplasms, Laparoscopy, Tomography- X-Ray Computed, Regression Analysis, Algorithms, Reference Standards


Concordance of the scoring algorithms based on serology, imaging and laparoscopy with primary surgical findings and surgical outcome in Epithelial Ovarian Cancer

Introduction

Griffith was the first to establish a clear relation between residual disease and survival (1,2). Since then, all the studies that addressed this issue found the same result: residual disease is the most important prognostic factor in these patients, i.e., survival is correlated to the surgical output. Bristow et al. published a meta-analysis including only cohorts of patients with stage III/IV ovarian cancer who received a “modern” platinum-based chemotherapy (3). He reported that survival of each cohort was significantly correlated to the rate of patients having a maximal cytoreductive surgery.

The use of radical surgery for patients with carcinomatosis in which optimal or complete resection can be obtained will have a positive impact on survival is a conceded reality. The only concern when attempting cytoreduction at all cost is the amount of morbidity or the mortality associated with such procedures. The decision is a fine balance between the benefits of an aggressive surgery that has a statistical value and the actual benefit imparted by that on patient’s life in a healthy way.  Selection of patients for upfront surgery is today mostly performed using clinical and serological criteria, imaging, laparoscopy and surgeon’s opinion (tumour board decisions). It would be desirable to have a magic criterion whereby all the decisions of interval or upfront cytoreduction can be made. It seems farfetched at this point, but continuous efforts to clarify the role of each measurable criteria will finally bring an answer to this difficult question. It is even more challenging for low resource settings to optimise their resources when providing the best option for their patients.

In the near future, molecular data could be used to help in the decision-making process (4). It appears logical to propose surgery when the expected rate of complete resection is high and to have an adapted approach in patients with predictable chemoresistance. (4) Still, low resource counties will have to use the age-old methods till these will be widely available and cost effective.

Aim of the study is to predict the outcome of cytoreductive surgery and the role of use of serologic markers such as CA-125, imaging modalities such as computed tomography (CT) and laparoscopy-based scores in the management of epithelial ovarian cancer in low resource settings.


Methods:

This was designed as an observational analytical study in a cross section of patients with advanced epithelial ovarian cancer undergoing primary cytoreductive surgery within defined inclusion and exclusion criteria. This study included the population accrued between March 2019 and January 2021 at the department of Gynaecologic Oncology of the Acharya Harihar Post Graduate Institute of Cancer regarding the role of laparoscopy in assessing the chance of optimal cytoreductive surgery in patients with advanced ovarian cancer. Inclusion criteria were clinical and instrumental (computed tomography, ultrasonography, or both) suspicion of diffuse disease of ovarian or peritoneal origin in patients planned for primary cytoreduction. Exclusion criteria were patients who were considered medically inoperable, including Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4, diagnosis of venous thromboembolism within six weeks of presentation, distant metastatic disease and surgically unresectable disease. All patients signed written informed consent agreeing to undergo all the procedures described and for their data to be used prospectively.

Pre?operative evaluation of the patients consisted of complete physical and gynaecological examination, assessment of Ca125 serum levels, Eastern Cooperative Oncology Group (ECOG) performance status, chest X?ray, abdominal?pelvic CT scan and sonography. All women with a clinical/radiological diagnosis of FIGO stage IIIC?IV ovarian/peritoneal cancer were submitted to laparoscopic fagotti scoring and then open fagotti scoring, before attempting cytoreductive surgery by standard laparotomy.

The CECT was reviewed by two different radiologists by Dowdy model(5). Diffuse peritoneal thickening (DPT) (defined as peritoneum > 4 mm thick in at least 2 of the following 5 areas: Lateral colic gutters, Lateral conal fascia, Anterior abdominal wall, Diaphragm, Pelvic peritoneal reflections) and ascites present on at least two-thirds of the CT cuts. The scoring was 0,1 ,2 according to none positive, one positive or two positive criteria.

Laparoscopic and Open scoring algorithm comprised of seven parameters as per original fagotti scoring(6–10): omental caking, peritoneal carcinomatosis, diaphragmatic carcinomatosis, mesenteric retraction, bowel infiltration, stomach infiltration, liver metastases . Each with a score of 2. The total would be the final score.

Figure 1


Surgical technique:

Forty- two patients underwent both laparoscopy and standard vertical laparotomy, sequentially. A longitudinal midline incision of approximately 10 mm was made just above or below the umbilicus. The rectus sheath was identified and incised longitudinally. The peritoneum was opened and a blunt 10-mm disposable trocar was introduced into the peritoneal cavity under visual and digital control. A second 5-mm trocar was then inserted into the midline under direct visual control. The entire abdominal cavity was carefully examined: the ovaries, fallopian tubes, uterus, pelvic peritoneum, serosa and mesentery of the large and small bowel, liver surface (nodules on liver capsule were not considered liver metastases), paracolic gutters and diaphragm. When necessary, an additional 5-mm trocar was used to facilitate dissection and bowel manipulation. Biopsy specimens of the ovaries, metastatic nodules or peritoneal surface were taken for frozen section to confirm the diagnosis of ovarian cancer. 

Standard surgery (including total abdominal hysterectomy with bilateral salpingo-oophorectomy; appendectomy; total/ infragastric omentectomy; peritonectomy, diaphragmatic stripping; bowel resection limited to the rectosigmoid, OR as necessary; and removal of bulky lymph nodes to the infrarenal paraaortic level) was completed to a minimal residual disease. Peritoneal carcinomatosis index was assigned to all cases. Surgical complexity was scored according to original Aletti (11)criteria. The completeness of cytoreduction (CC) was scored as proposed by Sugarbaker(12,13): CC0: no residual disease; CC1: residual nodules measuring less than 2.5 mm; CC2: residual nodules measuring between 2.5 mm and 2.5 cm; and CC3: residual nodules greater than 2.5 cm.

Optimal debulking was judged unfeasible in 3 patients after lap scoring; in these cases, cytoreductive surgery was abandoned for neoadjuvant chemotherapy followed by interval debulking surgery.

Consequently 39 patients were included in the final analysis.

 

Statistical Analysis:

All the parameters were tested for normality of distribution using standard normality tests. Descriptive statistics of normally distributed data is shown as Mean ± SD and non-normally distributed data as Median (25th percentile – 75th percentile). Data of all parameters were classified into two groups based on Complete cytoreduction score status as group 1 - CC = 0 and group 2 - CC ≠ 0. Data were compared between the two groups using unpaired t test or its non-parametric variant Mann Whitney U test. The parameters whose data showed significant differences in the comparison between groups 1 and 2 were incorporated as independent variables in the multiple regression analysis performed to identify the independent predictors of Complete cytoreduction score status. The parameters identified as independent predictors were subjected to Receiver Operator Curve characteristics analysis to assess their performance characteristics and identify cut-offs with optimal sensitivity and specificity. Concordance between the parameters to predict the complete cytoreduction score status was assessed using their respective cut-offs.  The level of statistical significance was set at p<0,05. All statistical analysis was performed using the software - GraphPad Prism, 9.0.2 (GraphPad Software, San Diego. USA)

 

Results

The patients were divided into two groups for better analysis. First group with complete cytoreduction(CC=0) and the other with incomplete cytoreduction(CC≠0). Both the groups were comparable in terms of age and parity. (table 1) The mean age was 48 years in the complete cytoreduction group and it was 50 years in the incomplete cytoreduction group. (figure 1) The mean parity of patients in complete cytoreduction group was 2.4 and in the incomplete cytoreduction group it was 2.8. Though the incomplete cytoreduction group had 56.5% of post-menopausal patients compared to the 43.5% in the complete cytoreduction group, it was not found to be statistically significant.

The median CA 125 levels in the complete cytoreduction group was 310 IU/ml, with an interquartile range of 38-626 IU/ml. It was 352 IU/ml in the incomplete cytoreduction group with the interquartile range of 236-802 IU/ml. These values were not found to be statistically different. (figure 2) The median CEA levels were 1.8ng/ml (interquartile range 1-5ng/ml) in the CC0 group and 2ng/ml (interquartile range 0.575-8.5ng/ml) in the CC≠0 group. It was also not significantly different between groups. (figure3)

Twelve patients had a CT score of 0 in the CC0 group, six with a CT score of 1 and five with a CT score of 2. Only five patients had a CT score of 0 in the CC≠0 group, another five with a CT score of 1 and another six with a CT score of 2. (figure 4)

Laparoscopic fagotti scoring was a median 4 (interquartile range2-4) in the CC0 group and 6 (interquartile range 4.5-8) in the CC≠0 group. (figure 5) Open score was also same with a median of 4 (interquartile range2-4) in the CC0 group and 6 (interquartile range 4.5-8) in the CC≠0 group. (figure 6)

The peritoneal carcinomatosis index was a median 6 (interquartile range 3-9) in the CC0 group and a median 9 (interquartile range 7-15) in the CC≠0 group. (figure7)

The surgical complexity score was a median 5 (interquartile 4-5) in the CC0 group and median 4 (interquartile 4-5) in the CC≠0 group. (figure 8)

Multiple regression analysis was done considering Age, CT Score, Fagotti Score, Open Score, PCI and SCS as independent variables. Fagotti score and SCS emerged as the independent predictors of Complete cytoreduction status. (table 2) The model explained 58.53 percentage of the variance in the outcome variable. Major predictor of the complete cytoreduction status was Fagotti score.

ROC curve was plotted to assess performance characteristics of these scores to predict CC0.When ROC curve was plotted for fagotti score, (figure 9, table 3) area under the ROC curve (fagotti score) was 0.8886 with a P value <0.0001. A value > 5 of fagotti score showed a balanced sensitivity of 75% and specificity of 86.96% for CC≠0 i.e., higher likelihood for CC≠0.

ROC curve for open score (figure 10, table 4) had an Area under the curve of 0.8533 with a P value 0.0002. A value > 5 showed a balanced sensitivity of 75% and specificity 82.61% for CC≠0, i.e., higher likelihood for. CC≠0

Though the ROC curve of SCS showed an area under the curve of 0.6223(95% CI 0.4399-0.8046), p value was not significant (p=0.1988). This could be because of the small sample size which fails to bring out the essential contribution of SCS to CC 0.

Considered all, serological markers prove to have no role at all when predicting a CC0 surgery is the question. Among the different scoring systems based on imaging, laparoscopic and open, upon multiple regression analysis, only fagotti and surgical complexity proved to be independent predictors. Open score doesn’t contribute independently to the prediction than what fagotti does. So, we assume that some component in Fagotti is contributing independently to prediction.

A lesser score for fagotti and a higher score for surgical complexity contribute towards prediction of CC0 as seen from the beta coefficient in the multiple regression analysis. The contribution of Fagotti is found to be higher than surgical complexity in this analysis. Since these two variables test independently to predict outcome, both can be relied upon. Considering that fagotti and open score has a significant p value in ROC plot, concordance between these two variables were analyzed. The analysis showed 95.7% concordance for CC0 between fagotti score and open score. It was 87.5% for CC≠0.

 

Discussion

In the present study both the groups, the one with complete cytoreduction and the other with incomplete cytoreduction were comparable in terms of age, parity and menopausal status. So, these could not have a say in the prediction for completeness of cytoreduction.

As per metanalysis by Kang et al in 2010(14), preoperative CA 125 serum level >500 U/mL showed a strong association with a risk of suboptimal cytoreduction. Nonetheless, CA-125 was insufficiently accurate to predict optimal and/or CCR (14). Since this meta-analysis, other evaluations of this test have provided heterogeneous results that cannot allow recommending CA-125 as a preoperative test for predicting resect ability of advanced ovarian cancers (15). Thus, there is no validated threshold of CA-125 level for predicting cytoreductive surgery outcomes.(15)CEA and CA 19.9 does not perform to raise a recommendation.

In this study as well, the median CA 125 levels in the complete cytoreduction group, 310 IU/ml, with an interquartile range of 38-626 IU/ml and 352 IU/ml in the incomplete cytoreduction group with the interquartile range of 236-802 IU/ml were not found to be statistically different. The median CEA levels 1.8ng/ml (interquartile range 1-5ng/ml) in the CC0 group and 2ng/ml (interquartile range 0.575-8.5ng/ml) in the CC≠0 group was also not significantly different. Thus, this study also agrees that serum markers do not contribute independently to the prediction of completeness of cytoreduction.

For assessment of the resect ability of ovarian cancer, cross-sectional imaging (CT or MRI) plays a critically important role(16).Rutten et al(17) identified 11 studies that described 13 models and concluded that there are no external validated studies with a good predictive performance for residual disease.Hu et al in their meta-analysis demonstrated that the eight preoperative CT findings had limited ability to predict the outcome of suboptimal cytoreductive surgery(18).

The predictive performance of preoperative CT images is variable due to interobserver variability, surgical outcome being highly dependent on the surgeon, the judgment of cytoreduction being subjective and that the characteristics of patients could impact the rates of cytoreduction. A study (19)pointed out that residual disease larger than 1 cm was present on early postoperative CT in almost half of the patients deemed to have optimally debulked disease at primary cytoreduction. A lack of accuracy of Contrast enhanced CT has been especially reported for bowel surface, mesenteric or small peritoneal deposits <5mm especially in the absence of ascites. This type of ovarian cancer spread is difficult to detect by CT but is an important limitation for complete or optimal cytoreduction(20).   

In this study, the Dowdy model (5)was chosen for a reason after considering Bristow(21) and Nelson(22) models. It was the simplest model that could be done by the surgeon itself before surgery. The simplicity makes it more acceptable to surgeons, makes it more reproducible even when showing 79% accuracy compared to the 92.7% for Bristow and 78% for Nelson models(17). The proportion of patients with CT score of 0 was high in the CC0 group, and the CT score of 2 was high in CC≠0 group. But, on multiple regression analysis CT score did not contribute independently to the prediction of completeness of cytoreduction.

Predictive models based on CT have been studied in a meta-analysis for their utility in predicting suboptimal cytoreduction and have been shown to have poor predictive value and their clinical use is not advised(18). Thus, the present study also concludes that CT findings alone do not appear to be sufficiently accurate to predict the results of cytoreductive surgery.

In this study, the surgical scoring models, Fagotti scoring, Open scoring, PCI scoring, Aletti surgical complexity scoring were individually compared in the CC0 and CC≠0 group. Both the Fagotti and Open score showed significant difference between the two groups. PCI score also showed a difference but was not significant up to that achieved by Fagotti and Open score. Surgical complexity scoring was not found to be significantly different between the two groups.

In the Multiple regression analysis, considering Age, CT Score, Fagotti Score, Open Score, PCI and SCS as independent variables, Fagotti score and SCS emerged as the independent predictors of Complete cytoreduction status. The model explained 58.53 percentage of the variance in the outcome variable with major predictor of the complete cytoreduction status as Fagotti score.

In the ROC curve plot for fagotti score, area under the ROC curve (fagotti score) was 0.8886 with a P value <0.0001. A value > 5 of fagotti score showed higher likelihood for CC≠0.ROC curve for open score had an area under the curve of 0.8533 with a P value 0.0002 and a value > 5 showing higher likelihood for CC≠0. Though the ROC curve of SCS showed an area under the curve of 0.6223(95% CI 0.4399-0.8046), p value was not significant (p=0.1988). This is expected because of the small sample size which fails to bring out the essential contribution of SCS to CC 0.

So, this study shows fagotti and open scoring to be able to predict the completeness of cytoreduction. Open scoring did not offer anything extra from Fagotti as we used the same scoring algorithm for both, though some points need mention. One case of porta hepatis deposit was seen in the Lap and missed in open scoring (lap score 4/open 2/ CC≠0) and two cases of posterior diaphragmatic deposit which were seen only because of lap scoring. A case of Pouch of douglas deposit (though did not make a difference as there were other peritoneal deposits which definitely added and lead to the score equalization), another case of mesenteric invasion (lap score 8/open 10/ CC≠0) and mesenteric lymph nodes in another (lap score 4/open 6/ CC≠0) were hidden in Lap scoring but evident in open scoring. PCI also is a reliable predictor but as quite understandable doesn’t offer anything extra than what Fagotti has to offer considering the fact that just one component of fagotti is peritoneal carcinomatosis. SCS had an independent contribution, the extent of which couldn’t be evaluated with the small sample size.

The discrepancy in laparoscopic and open scoring seen in this study might need an explanation. Considering the set up where the study took place with limited resources, the staging component usually takes the brunt as maximum initial 15 minutes is attributed to it. The sites like posterior diaphragm and porta hepatis are easily missed in this hurried approach and were detected because of Lap scoring. These sites are easily cytoreduced as they were peritoneal disease and contributed to the outcome. Though lap scoring missed POD deposit in one and mesenteric deposit in two, they did not make any difference. As in the POD deposit case, there were other peritoneal deposits which compensated the score and in the two cases of mesenteric deposit which were missed, the cytoreduction was anyways not complete which means the scoring difference did not affect the outcome. So, ultimately Fagotti scoring helped achieve CC0 in more cases than not. Though one can argue that the missed sites in open scoring would have not been considered in cytoreduction and still been considered CC0 in conventional way and would have been the case of almost 50% cases of wrongly assumed CC0(19).It is desirable to be able to keep a check in such set ups with a laparoscopic scoring to further add to cytoreduction than to worry about the mesenteric deposits that would anyways be not cytoreduced. This is a universal issue, with even better set ups missing the same parameters and is the Achilles heel of laparoscopic scoring model.(9,23,24)

In a Cochrane review concerning the accuracy of laparoscopy in predicting the resect ability of advanced ovarian cancer (23),eighteen studies were included, making a non-pooled analysis of 1563 cases. The review showed that potential false positive cases appear to have no clinical implication as survival after neoadjuvant chemotherapy is not inferior(25,26). Conversely, more attention should be paid to the risk of false negative patients (those who were predicted to have complete or optimal cytoreductive surgery but who had in fact a suboptimal surgery at laparotomy). This failure in the predictive laparoscopic procedure leads to unsuccessful cytoreductive surgery and, as a consequence, unnecessary morbidity, cost and delayed chemotherapy (23,27–29). A good concordance has been shown between the laparoscopic PIV score and control scoring by laparotomy (24).In the present study also the lap score and open score were concordant. Concordance has been shown to vary by localization and was lowest for the mesentery (84.6%) and bowel (74.4%) (24).In this study also mesentery  scoring was mostly discordant not favouring Laparoscopy. But, the additional cases of diaphragmatic and porta hepatis deposits detected by laparoscopic scoring made a difference in cytoreduction, favouring laparoscopy.

 

Conclusion

After consideration of the serum markers, CT score model, Laparoscopic and open score models in their ability to predict cytoreduction, it was concluded that Fagotti laparoscopic score has the best concordance with open findings and the best ability to predict completeness of cytoreduction. Further studies with higher patient number will be required to comment on the surgical complexity score’s contribution to predicting completion of cytoreduction. It is recommended to consider laparoscopic Fagotti scoring for all patients decided for primary cytoreduction before laparotomy.

 

Limitations:

Considering the low resource setting with high patient load in the study, most of the suspected advanced ovarian cancer patients get triaged in OPD setting itself, mostly based on image guided biopsy, to the NACT arm. So, the evaluation basically contrived to triage only the patients already decided for primary cytoreduction by initial evaluation. That explains only 3 patients going to NACT arm after laparoscopic scoring.

As already stated, the characteristics of patients could impact the rates of unresectable disease. In the study setting most of the patients present in poor general condition making extensive surgeries not the best option even in average set up. There were instances of patients denying bowel resections due to fear of colostomies in the series, thus making them not completely cytoreduced even when expected to be.

The judgment of suboptimal vs. optimal cytoreduction is subjective if there is no postoperative CT evidence, especially when judged by only one surgeon. This could also be considered as a limitation.

 

Future Directions:

Application of models evaluated in well-resourced settings without being tried out in local settings and expecting the same results and observations may not be the best approach for resource limited countries. Future approaches should always consider the high volume, low resource setting, dealing with a less healthy cohort of people and decide what would be the best for them after evaluations of models in the local settings itself.

 

Conflicts of interest

No conflicts of interest for any of the authors.

 

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