Epidemiology of psychiatric disorders following cytoreductive surgeries plus hyperthermic intraperitoneal chemotherapy: a prospective cohort analysis

The peritoneal surface malignancy (PSM) is an advanced disease, the prognosis of which has been radically improved since the development of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC). These procedures are associated with many complications. However, very few data are available regarding the psychiatric morbidities that might occur. The present study assessed the epidemiology of depressive mood and anxiety during the 6 months following the procedure. The analysis of a prospective cohort that included patients who underwent CRS with or without HIPEC between December 2016 and December 2019 was performed. A total of 115 patients were included. During the 6-months follow-up, the mean (SD) Hospital Anxiety and Depression Scale –D (HADS-D) score was 7.8 (48) and a significant increase compared with the pre-operative period (t(49) = − 4.36, p < 0.005) was found. Thirty-seven patients (32%) had a HADS-D score higher than 7. The incidence of a HADS-D score higher than 7 during the follow-up was 0.05 patient per patient-month. Anxiety and the overall mental disorders intensity scores also increased. The results showed an important increase of mental disorders and their intensity during the 6-months following a CRS with or without HIPEC.

The peritoneal surface malignancy (PSM) is an invasion of the peritoneal serosa due to malignant cells from a heterogeneous group of primary tumors that has a poor prognosis 1 .Despite existing primary peritoneal malignancies, the epidemiology of PSM is mainly due to the metastatic spread of ovarian and colorectal cancers on the peritoneal serosa 1,2 .This condition used to have a poor prognosis, the 10 year survival is lower than 20%, regardless of the primary tumor site 3,4 .In the past decades, its prognosis has been radically improved since the development of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) 1 .CRS is a complex surgical intervention that lasts up to 10 h to meticulously excise all macroscopic manifestations of the disease.In addition, to target microscopic manifestations, chemotherapy heated to temperature between 42 and 43 °C can be administered 5 To achieve a complete resection of the macroscopic disease a series of intricate steps that includes digestive resections, hepatectomies, splenectomies, peritonectomies, and anastomoses is often necessary 1 .Unfortunately, these surgical procedures are prone to a significant morbidity 5,6 , including veno-thrombotic events, infections, anastomotic leaks, fistulas, and complications due to long-term stays in intensive care units 2,5 .In a quarter of the patients, these complications lead to readmission during the 6 months following the procedure, up to 13% require another surgery 7 .
The study questionnaires were filled-in by the patients before the surgery and at each visit during their followup at the inclusion center.
For the screening of depression and anxiety, we respectively used in the dedicated subscales the cutoffs of 7 and 9 to maximize combined sensitivity and specificity 11 .
The quality of life was assessed using the Global Health Status (GHS) score, extracted from the EORTC-QLQ-C30 12 .
Analyses.Only patients for whom a HADS-D score was available in the 6 months following the surgery (primary outcome) were included.
Descriptive statistics were expressed as means and standard deviations, and counts and percentages.For dependent variables, Student-t test was used to assess the differences between scores at the time of the inclusion and during the 6-months follow-up.The Chi-square test was used to assess the difference between positive screenings in depression and anxiety at the time of the inclusion and during the 6-month follow-up.The association of HADS scale and subscales scores with the GHS was assessed using the Pearsons' correlation and the Chi-square test.
All analyses were performed on ISM SPSS Statistics 21 and the differences were considered statistically significant using an alpha risk of 0.05.

Ethics approval and consent to participate.
All patients signed an informed consent to be included in the BIG-RENAPE prospective cohort (ClinicalTrial: NCT02823860).The database obtained all legal authorizations in 2012 and was approved by the institutional ethics committee of the Hospices Civils de Lyon in compliance with the French regulation.The methods were carried out in accordance with the relevant guidelines and regulations.

Results
Among the 305 patients included in the cohort during the study period, 115 had an available HADS-D score during the 6 months following the surgery and were thus included in the analysis.
Primary outcome.The mean (SD) HADS-D Score during the 6-months follow-up was 7.8 (4.8) and 37 patients (32%) had an HADS-D score higher than 7.The incidence of HADS-D score higher than 7 during the 6-months follow-up was 0.05 patients per patient-month.

Secondary outcomes (Table 2).
The mean (SD) HADS score during the 6-months follow-up was 13.3 (7.5), with a significant increase in HADS scores between the assessment at the time of inclusion (mean HADS score = 5.6) and the assessment during the 6-months follow-up (p < 0.05).Similarly, the HADS-D score significantly increased from 5.1 (4.5) at the time of inclusion to 7.8 (4.8) during the 6-months follow-up (p < 0.05).There was no significant difference in HADS-A scores between the time of inclusion and the 6-months followup.The mean (SD) GHS score significantly decreased from 67.1 (23) at the time of inclusion compared with 54.4 (22.0) during the 6-months follow-up (p < 0.05).
The number of HADS-D scoring higher than 7 significantly increased between the time of inclusion and during the 6-months follow-up (chi2 = 9.25, (Df = 2) p = 0.01).
The number of HADS-A scoring higher thant 9 significantly increased between the time of inclusion and during the fol6-months follow-up (Yates' correction applied, chi2 = 7.36, (Df = 2), p = 0.007).
The quality of life measured by the GHS significantly decreased between the time of inclusion and during the 6-months follow-up (t = 2.26, (Df = 16), p = 0.038).There was no statistical correlation between the HADS-D and GHS scores (r = − 0.28, p = 0.084) nor between the HADS and GHS scores during the 6-months follow-up (r = − 0.23, p = 0.15).

Discussion
The present study showed an increase of all scores related to depressive mood, anxiety and mental disorders during the 6-months following CRS in PSM.Theses results highlighted a statistically significant increase of the incidence of depression during the 6-months following a CRS.Although a significant decrease of the healthrelated quality of life score was found, there was no correlation with mental disorders scores.
The present results highlighted the existence of mental disorders, including depression and anxiety disorders, during the 6 months following a CRS.These results complete those of a recent prospective cohort reported by Oswald et al. 13 ; the authors explored the levels of anxiety, depression and stress following CRS with HIPEC until discharge.In this prospective cohort of 169 patients, the authors did not identify increased scores in depression nor stress.However, increased scores of anxiety were reported from surgery to discharge.We do not consider the results of the present study as conflicting with those of this study, as the screening tools and the period of assessment were different between the two studies.However, in both studies, the results reported an increased risk of mental disorders in patients who underwent a CRS.Both studies suffered from a major limitation related to the fact that the cases were not defined using the gold standard 14 .
Major depressive disorders are defined by the fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM V) as the presence of at least 5 symptoms, among a list of 9, during the same two week period, in addition to: (i) a significant distress and (ii) the exclusion of any attributable cause, better scientific explanation or history of manic or hypomanic episode.Additionally, as recommended by the DSM V, mental disorders should be diagnosed following a semi-structured clinical interview by a psychiatrist 14 .However, the use of a screening tool is relevant to provide preliminary data regarding the epidemiology of mental health in this population.Additionally, as the depressive disorders are often unrecognized, Gelenberg et al. underlined that using tools to diagnose major depressive disorders is a relevant strategy to improve the diagnosis 15 .
Moreover, due the use of a pre-existing database, the study was restricted to the outcomes collected during the design of the database.For instance, post-traumatic stress disorders that might affect patients following their stay at the intensive care unit following CRS were not collected..This might be explained by the lack of evidence regarding the association between mental health and surgical outcomes conversely to nutritional or physical issues that have been extensively studied and led to peri-operative interventions 16 .Overall, in addition to Oswald et al. study, the present results advocate for future research to evaluate the causality and the potential impact of mental disorders following peritoneal cancer surgeries on the patients outcomes.Based on the model of nutrition and physical care in cancer surgery, this might enable the development of mental health interventions to prevent, identify and treat mental disorders in the perioperative period.

Conclusions
The results showed an important increase of mental disorders and their intensity during the 6-months following a CRS with or without HIPEC.This argues to develop interventions in order to address mental health issues in such settings.

Table 1 .
Sample characteristics (the indicated sample size is the sample of patients for whom the information was available).