Prognostic factors for ovarian metastases in colorectal cancer patients

Purpose The aim of this study was to analyze prognostic factors for ovarian metastases (OM) in colorectal cancer (CRC) using data from a Chinese center. In addition, the study aimed at developing a new clinical scoring system for prognosis of OM of CRC patients after surgery. Patients and methods Data of CRC patients with OM were collected from a single Chinese institution (n = 67). Kaplan-Meier analysis was used to evaluate cumulative survival of patients. Factors associated with prognosis of overall survival (OS) were explored using Cox’s proportional hazard regression models. A scoring system to determine effectiveness of prognosis was developed. Results Median OS values for patients with or without surgery were 22 and 7 months, respectively. Size of OM, number of OM, peritoneal metastasis (PM), Peritoneal cancer index (PCI), and completeness of cytoreduction (CC) were associated with OS of patients through univariate analysis. Multivariate analysis using a Cox regression model showed that only CC was an independent predictor for OS. Three variables (the size of OM >15cm, PCI ≥ 10, and carcinoembryonic antigen (CEA) >30 ng/mL) assigned one point each were used to develop a risk score. The resulting score was used for prognosis of OS. Conclusion Surgical treatment of metastatic sites is effective and safe for CRC patients with OM. CC-0 is recommended for improved prognosis. The scoring system developed in this study is effective for prediction of OS of patients after surgery. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-021-02305-3.

Cytoreductive surgery (CRS) is referred as a therapeutic strategy due to limitations associated with chemotherapy [9,[12][13][14][15]. CRS has revolutionized treatment of OM in CRC patients [16]. Patients achieve notable survival benefits (median OS of 36 to 43 months) after undergoing CRS compared with systemic chemotherapy [3]. However, to the best of our knowledge, recurrence, and distant metastasis still exist after detection, and currently, few studies report on the risk stratification and selection of patients who may benefit from surgical oophorectomy. Therefore, it is necessary to develop a clinical criterion for selecting patients to undergo surgical oophorectomy.
Data used in this study were retrieved from a single Chinese center. Data were used evaluate prognostic factors for CRC patients with OM. In addition, a clinical scoring system was developed using pre-and intraoperative factors to predict survival of CRC patients. The findings of this study will provide information and treatment strategies for clinicians and serve as a basis for further research.

Ethics and patients
CRC patients (n = 67) presenting with OM from January 2010 to July 2019 were included in this study. Details of surgical oophorectomy were analyzed for 54 patients because 13 patients did not undergo surgery or underwent surgery in a different hospital. The study was approved by the Institutional Review Board of the Second Affiliated Hospital of Zhejiang University School of Medicine. The study was conducted according to the Declaration of Helsinki, Fortaleza, Brazil, 2013. All patients included in the study provided signed informed consent.

Inclusion and exclusion criteria
Patients were enrolled into the study according to the following criteria: (1) diagnosis of CRC with synchronous or metachronous OM; (2) Eastern Cooperative Group (ECOG) performance status 0 or 1, and no extra-abdominal disease on radiological investigation; and (3) extent of OM evaluated either via contrast-enhanced computed tomography (CT) or magnetic resonance imaging of the ovaries, and treatment was discussed by the multidisciplinary cancer treatment team (MDT). Exclusion criteria were as follows: (1) follow-up time < 12 months from the date of diagnosing OM and (2) extraabdominal metastasis.

CRS/HIPEC
Completeness of cytoreduction (CC) was classified as one of four grades (CC-0, -1, -2, and -3) based on the size of residual tumors after CRS. CRS was performed to remove all macroscopic OM or leave lesions < 2.5 mm (CC-0/1), which was considered optimal cytoreduction. Extent of disease was assessed using peritoneal cancer index (PCI) score, as described by Jacquet and Sugarbaker [17]. HIPEC was performed immediately after the abdomen was closed in the operating room. Mitomycin C (30 mg) or oxaliplatin (400 mg) was administered for 60 min at 43°C in all cases. After postoperative recovery, patients received systemic chemotherapy for a maximum of 24 weeks.

Clinical follow-up
A follow-up was carried out for all patients in the outpatient unit approximately 2 weeks after treatment, and at least every 3 months for 2 years, then every 6 months after the first 2 years. Carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and carbohydrate antigen 125 (CA125) markers, and CT scans of the abdomen, pelvis, and thorax, were assessed at each followup visit.

Clinicopathologic features
A total of 67 CRC patients diagnosed with OM between January 2010 and June 2019 in our cancer center were included in this study ( Fig. 1 Most cases (79.6%) presented with lymph node invasion, and the number of lymph nodes invaded was ≥ 4 in 19 patients (35.2%). More than 50% patients presented with PCI ≤ 10 and underwent CC-0/1 in our center. Demographic and histologic data of patients are summarized in Table 1.

Survival outcomes
Median follow-up time was 68 (range, 1 to 85) months from the date of OM diagnosis. Median OS for all patients was 22 months, with overall 1-and 3-year survival rates of 66.7% and 30.4%, respectively. A total of 4 patients rejected surgery after OM diagnosis. Median OS for the 4 patients was 7 months compared with 22 months of patients who underwent CRS (Fig. 2).
Analysis of predictors using Kaplan-Meier method showed that size of OM (P = 0.018), presence of PM (P= 0.016), PCI (P = 0.003), and CC score (P < 0.001) were significantly associated with OS (Table 2). However, vascular invasion, perineural invasion, CEA, CA125, or the number of lymph node invasion were not correlated with survival time. In addition, demographic and histologic data, including age, T stage, N stage, grade, pathological subtype, and primary cancer site, were not significantly correlated with survival time (Supplement Table 1). Factors with P value less 0.1 were used for multivariable analysis, and only incomplete cytoreduction was identified as an independent predictor for poor OS (CC >1; HR, 3.782, 95% CI, 1.873 to 7.637; P <0.001) ( Table 2, Fig. 3).

A new clinical risk score for selecting suitable OM
A new clinical risk score was developed using significant indicators for OS in Kaplan-Meier method including PCI and size of OM. CEA which is important for CRC was also included. Although progression of disease at the level of CC was an independent predictor of prognosis as shown by multivariate analysis, not all patients received surgery. Furthermore, addition of this factor into the risk score model did not improve its prognostic value; therefore, it was omitted from the final model. The score for the corresponding indicators HR value was rounded up to the integer value.
Clinical risk score of all patients was calculated using complete data. The new clinical risk score in patients was calculated with the actual distribution from 0 to 7 points and a median of 3 points and a mode of 3 points (Fig. 4A). Patients were divided into < 3 groups and acuity grouping for subsequent analysis using cut-off value of 3 points (median). A score < 3 patients resulted in a high CC-0 ratio (88.2%), and most patients with a score ≥ 3 points did not reach tumor removal stage (Fig. 4B). A high score was positively correlated with poor overall survival. Patients who scored <3 (low risk) had 1-, 3-, and 5-year survival of 76.5%, 44.6%, and 37.2%, respectively, and median survival of 36 months. Patients who scored ≥ 3 (high risk) had a 3-year survival of 16.5% with no survivors beyond 5 years and median survival of 12 months (Fig. 4C).

Discussion
Previous studies have explored factors associated with prognosis of CRC patients with OM. However, this is the first study to develop a new clinical risk score to help in preoperative or intraoperative decision making. OM affects young women, develops rapidly, and is relatively chemoresistant; therefore, there is a need to develop effective treatment of OM patients [9]. Previous studies have reported controversial results on CRS for CRC  [16,[18][19][20]. However, some studies report that CRS approach is ineffective [21,22]. In this study, median OS for CRC patients with OM group who underwent surgery was 22 months, compared with median OS of 10 months for patients receiving palliative treatment reported by Lee et al. [11]. Previous studies report that CRS affects long-term prognosis and recurrence of patients with CRC [23][24][25][26][27][28][29] and similar results were reported in our study. CRC patients with OM who achieved CC-0 showed a median OS of 36 months, whereas patients who did not achieve CC-0 showed a median OS of 3 months. Multivariate analysis showed that incomplete cytoreduction is an independent risk factor for OS. However, HIPEC was not associated with OS of CRC patients in our study, which can be attributed to the small sample size. The results of the current study show that CRS should be performed on CRC patients as it is safe, feasible, and effective for treatment of diverse advanced tumors. However, some researches showed the influence of ovariectomy for female [30][31][32]. Ovariectomy will cause menopause in young patients, which makes a sudden perimenopausal syndrome, and the more severe symptoms than natural [30]. Besides, a cohort study in Britain reported that early menopause is a risk of ischemic stroke (early menopause vs natural menopause, HR = 1. 5, 95% CI 1. 01~2. 25) [31]. According to Mayo Clinic Oophorectomy and Aging Cohort Study, early menopause caused by surgery is associated with osteoporosis, worse neurocognitive performance, and symptoms of depression or anxiety [32,33].
The findings of this study show that complete resection of ovarian metastasis is positively correlated with a better prognosis. However, CRC patients with OM to undergo surgery should be selected carefully. Preoperative assessment of suitable patients for aggressive treatment mode can reduce switching operation rate, incomplete tumor surgery rate, and perioperative mortality. Currently, there is no unified standard but some considerations include informed consent and will of patient, ECOG < 2, no serious complications, acceptable quality of life, asymptomatic, lack of tumor progression during chemotherapy, absence of extravasation, resectable liver metastases <= 3, intestinal stenosis <= 1, no widespread intestinal disease, no biliary or ureteral obstruction, stomach liver toughening with involvement < 5 cm, no mesenteric root or pancreatic infiltration, possibility of completing CC0-1, and PCI < 20; however, prognosis of patients are different. Several prognostic scoring system have been reported as references for CRC patients with PM, including Colorectal Peritoneal Score [34], Peritoneal Surface Disease Severity Score (PSDSS) [35], and Colorectal Peritoneal Metastases Prognostic Surgical Score [36,37]. Pelz et al. developed a PSDS S based on clinical symptoms, PCI, and histology to serve as a prognostic tool for overall survival for clinicians and researchers. Simkens et al. evaluated peritoneal surface disease PSDSS and suggested COMPASS, including age, PCI, locoregional lymph node status, and signet ring cell histology. However, no other single factor examined reliably differentiated suitable patients to undergo surgery from CRC patients with OM who met an early demise. Therefore, we sought to develop a scoring system using multiple factors to provide information on pre-operative or intra-operative decision making. The alternative system uses 3 variables including PCI, size of OM, and CEA > 30ng/mL. In order to maximize clinical utility, only variables known preoperatively and/or intraoperatively were included. Therefore, although completeness of OM resection was prognostic factor for survival as shown by multivariate analysis, CC was not used in building our predictive model. All three factors in the final scoring model were weighted based on comparable hazard ratios (2.295, 2.536, and 0.899 for PCI, size of OM and CEA > 30ng/mL, respectively). A group of patients (risk score ≥ 3) who performed poorly after resection were identified using this proposed risk scoring system. These outcomes were consistent with modern chemotherapy outcomes (median OS=12). The findings show that higher score is correlated with poor prognosis. High clinical risk score was associated with significant decrease in proportion of CC-0 patients, whereas the proportion of CC-3 or CC-4 patients was significantly increased. These findings imply that CC-3 or CC-4 patients should not undergo resection. In contrast, patients with < 3 points showed comparable survival to patients with surgery.
Prognostic factors were analyzed and a new clinical risk score for CRC patients with OM was developed using data from our center; however, our study had some limitations. First, this was a retrospective study; therefore, it had potential bias. Second, we used a sample size comprising 67 CRC patients with OM. These limitations could be ameliorated by recruitment of more patients for inclusion in a future prospective study.    Studies including more samples should be carried out to assess effectiveness of treatments and explore effective prognostic factors for CRC patients with OM.

Conclusion
In summary, surgery is an effective and safe treatment approach for CRC patients with OM. In addition, surgery of the metastatic site should be recommended for CRC patients with OM to achieve CC-0. OM should not be considered an absolute contraindication to curative resection; however, appropriate selection is important. The proposed scoring system provides a basis for identification of a subset of patients who do not benefit from resection.