ABSTRACT
Background
The peritoneum is the third most prevalent location for metastases of colorectal cancer. In patients with resectable disease, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS‐HIPEC) is the preferred treatment in the Netherlands, achieving median overall survival (OS) of 36–42 months. However, during explorative laparotomy, CRS‐HIPEC may appear unfeasible. Evidence on how such non‐therapeutic laparotomies affect prognosis is limited.
Methods
This retrospective cohort study included all non‐therapeutic laparotomies performed between 01 and 01‐2010 and 01‐01‐2022 in two Dutch tertiary HIPEC‐centers. Patient, tumor and treatment characteristics, postoperative morbidity, and survival outcomes were analyzed and compared to existing literature.
Results
In total, 108 patients underwent a non‐therapeutic laparotomy (discontinued CRS‐HIPEC). The main reason was that peritoneal disease was too extensive (56%). Severe postoperative complications (Clavien–Dindo ≥ 3) occurred in 9%. Following a non‐therapeutic procedure, 55% of patients received tumor‐directed palliative treatment. Median OS of the entire cohort was 6.5 months (95% CI 5.1–8.0). Palliative systemic therapy was the only factor significantly associated with improved OS (12.6 vs. 2.9 months, p < 0.001).
Conclusions
Non‐therapeutic laparotomies are associated with decreased survival in patients with extensive peritoneal metastases. Reducing their occurrence is essential. Advances in diagnostic modalities, including MRI, FAPI‐PET, artificial intelligence, and developments in bidirectional treatments, may improve preoperative selection and offer alternative therapeutic options. Further research is required.
Keywords: colorectal cancer, irresectable disease, non‐therapeutic laparotomy, palliative treatment, peritoneal metastases
1. Introduction
Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide, being diagnosed in about 2 million patients in 2020 [1]. Metastases occur in 20% of patients, mostly in the liver [2]. The second most prevalent site for isolated metastases is the peritoneum, occurring in 6% of patients at the time of diagnosis and 5.5% of patients during follow up after a curative resection of the primary tumor [3, 4]. The prognosis of patients with colorectal peritoneal metastases (CPM) is dismal, as only 10% of patients are eligible for curative intent treatment, being cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS‐HIPEC) [5]. CRS‐HIPEC is an important treatment option for selective patients with CPM and results in survival rates of 36–42 months depending on the extent of disease [6, 7, 8]. In patients who are ineligible for CRS‐HIPEC, tumor directed palliative systemic treatment and best supportive care remain as options, with recent population‐based study showing median overall survival (OS)‐rates of 12 and 2 months, respectively [5].
Whether a patient is eligible for CRS‐HIPEC depends on the possibility for a macroscopic complete cytoreduction. Massive involvement of the small intestine, resulting in short bowel syndrome after radical resections is another well‐known contra‐indication. Next, CRS‐HIPEC should not be performed when the peritoneal disease is too extensive to obtain radical resection (CC‐0 or CC‐1). The extensiveness of disease is indicated by the PCI‐score [6, 7, 9]. In the Netherlands, consensus was reached on a cut‐off value of 20 out of 39 [6]. If peritoneal disease is more extensive, research has shown that performing CRS‐HIPEC is non‐beneficial for OS, and the extent of surgery is too high or the disease is irresectable [10]. Other eligibility criteria for CRS‐HIPEC are the absence of systemic metastases (mostly liver‐ and lung metastases), and having an overall condition fit for surgery [6].
Despite an extensive diagnostic workup, it may occur that during the CRS‐HIPEC‐procedure complete cytoreduction appears not to be feasible, resulting in termination of the intended operation. Previous research has shown that such non‐therapeutic laparotomies occur in about a quarter of planned CRS‐HIPEC procedures [11, 12]. About a decade ago, diagnostic laparoscopy (DLS) was added to the workup prior to CRS‐HIPEC to exclude patients with too extensive disease. However, this is not broadly implemented, and it is not always possible due to adhesions. Current literature on survival outcomes includes all patients with ineligible disease, not only those whose surgical procedure is discontinued [11, 12]. Median OS according to this evidence was especially lower in the group of patients who were deemed ineligible for CRS‐HIPEC due to too extensive peritoneal disease. However, regardless of the reason for the non‐therapeutic laparotomy, this existing evidence shows a decrease in median OS in patients who have a non‐therapeutic laparotomy as compared to CRS‐HIPEC. The median OS is especially lower in the group of patients who do not receive palliative treatment afterwards, but only best supportive care (BSC) [11, 12].
The present study was conducted to gain a more in‐depth analysis on the characteristics, performance and outcomes of those patients in whom CRS‐HIPEC appeared not feasible during exploratory laparotomy. The aim of this study was to explore the course following non‐therapeutic laparotomy.
2. Materials and Methods
2.1. Setting
Data was collected in two specialized Dutch HIPEC‐centers, the Amsterdam University Medical Center and the Catharina Hospital Eindhoven. Both centers adhere to the national protocol for CPM [13, 14]. All Dutch citizens are compulsorily insured for healthcare, making CRS‐HIPEC and any palliative treatment accessible and reimbursed when indicated [15].
All patients scheduled for CRS and HIPEC are included in a prospective institutional database which includes data on patient characteristics, details of the operative procedure, post‐operative complications and length of stay. For the purpose of the current study these data were later completed with additional data on palliative treatment after discharge and survival. This database, and this study as an extension, were approved by a Central Ethics Committee (MEC‐U, Nieuwegein, the Netherlands; Non‐WMO 2015‐11) and conducted in accordance with the Declaration of Helsinki.
2.2. Patient Selection
All adult patients ( > 18 years) that were planned for CRS‐HIPEC in the Amsterdam University Medical Center and the Catharina Hospital Eindhoven between 01‐01‐2010 and 01‐01‐2022 were enrolled. Patients were included in this study if they were planned for CRS‐HIPEC, but intraoperatively the procedure was discontinued, before any debulking was performed. Patients were excluded if CRS‐HIPEC was cancelled because peritoneal disease was absent perioperatively. Within this study period, the use of DLS as part of diagnostical pre‐operative workup has been implemented in standard care in the Netherlands. During this period, upfront CRS‐HIPEC has been the standard of care for patients with resectable peritoneal metastases. Additionally, no differences in eligibility criteria for curative intent treatment (i.e. CRS‐HIPEC) were implemented within this period. Heterogeneity within this group does exist due to difference in standard of chemotherapy in case of unresectable disease.
2.3. Data Collection
Data on the patient characteristics, tumor characteristics and treatment outcomes were collected from the electronic patient files. Age was determined based on the date of the non‐therapeutic laparotomy. Vital status was based on data from the Dutch municipal administrative database, which contains data on all Dutch current, former and deceased citizens. Survival was defined as the time between date of the non‐therapeutic laparotomy and date of death. Postoperative complications were analyzed according to the Clavien‐Dindo classification (CD) [16]. CD complications were scored until 90 days postoperatively, and in case of multiple complications, the highest CD grade complication was reported.
2.4. Statistical Analysis
Descriptive statistics were used for clinicopathological characteristics and surgical, post‐operative, and survival outcomes. Categorical and dichotomous variables were shown as n (%) and continuous variables as median (IQR). In case of missing data, percentages were based on the available data. Overall survival (OS) was analyzed using Kaplan‐Meier curves and significance was determined using the Log Rank test. Statistical significance was defined as p < 0.05 and analyzed with log‐rank tests. Hazard ratio (HR) was determined using Cox‐Regression tests. All analyses were performed using SPSS Statistics for Windows, Version 28.0. Armonk, NY, USA: IBM Corp.
Outcomes were eventually compared to results of existing literature, as no group of patients was present for comparison within the database.
3. Results
3.1. Study Population
Of the 883 patients planned during the study period for CRS‐HIPEC for CPM, 108 patients underwent a non‐therapeutic laparotomy due to inoperable mCRC (Table 1). Median age was 65.9 years, and a majority of patients had an ASA classification II (63%), synchronous disease (55%) and had not undergone a previous CRS‐HIPEC (92%). Primary tumors were mostly right sided (57%) and median PCI‐score was 24.0 (IQR 20.3–28.0). A DLS was performed in 44% of patients.
Table 1.
Patient and tumor characteristics.
| Total (n = 108) | |
|---|---|
| Variable | N (%) or median (IQR) |
| Gender | |
| Male | 45 (42%) |
| Female | 63 (58%) |
| Age at date of procedure | |
| 65.9 (59.2–70.9) | |
| Body mass index (BMI) before HIPEC a | |
| 24.8 (22.3–28.4) | |
| ASA classification | |
| I | 8 (8%) |
| II | 67 (63%) |
| III‐IV | 32 (30%) |
| Unknown | 1 |
| Primary tumor location side | |
| Right sided | 61 (57%) |
| Left sided | 35 (32%) |
| Rectum | 12 (11%) |
| Histology | |
| Adenocarcinoma | 69 (68%) |
| Mucinous | 21 (21%) |
| Signet ring cell | 11 (11%) |
| Unknown | 13 |
| Differentiation grade | |
| Well/moderate | 62 (65%) |
| Poor/undifferentiated | 22 (35%) |
| Unknown | 13 |
| T‐stage | |
| T1‐3 | 43 (49%) |
| T4 | 44 (51%) |
| Unknown | 21 |
| N‐stage | |
| N0 | 21 (24%) |
| N1 | 33 (38%) |
| N2 | 34 (39%) |
| Unknown | 20 |
| PCI‐scoreb | |
| 24.0 (20.3–28.0) | |
| Onset of peritoneal metastases | |
| Synchronous | 59 (55%) |
| Metachronous | 49 (45%) |
| Previous HIPECa | |
| No | 99 (92%) |
| Yes | 9 (8%) |
| Diagnostic laparoscopy/laparotomy | |
| Not performed | 60 (56%) |
| Performed | 48 (44%) |
HIPEC = Hyperthermic Intraperitoneal Chemotherapy.
PCI‐score = Peritoneal Cancer Index‐score; only measured in patients after 1‐1‐2013.
3.2. Treatment Characteristics
Most patients did not receive neoadjuvant treatment prior to the non‐therapeutic laparotomy (84%). Median procedure time was 95.0 min (IQR 71.0–138.0). Most prevalent reason for a non‐therapeutic laparotomy was presence of too extensive disease (56%), followed by extensive small bowel involvement (28%) (Table 2).
Table 2.
Treatment characteristics.
| Total (n = 108) | |
|---|---|
| Variable | N (%) or median (IQR) |
| Neoadjuvant systemic treatment | |
| No | 91 (84%) |
| Yes | 17 (16%) |
| Procedure time in minutes | |
| 95.0 (71.0–138.0) | |
| Reason non‐therapeutic laparotomy | |
| Extensive disease | 60 (56%) |
| Small bowel involvement | 30 (28%) |
| Anatomically irresectable | 9 (8%) |
| Systemic metastases | 9 (8%) |
| Palliative procedures during non‐therapeutic laparotomy | |
| Palliative resection | 13 (12%) |
| Ostomy | 13 (12%) |
| Bypass | 14 (13%) |
| Adhesiolysis | 16 (15%) |
| Hospital stay in days | |
| 5.5 (4.0–9.0) | |
| Palliative systemic treatment | |
| No | 45 (45%) |
| Yes | 54 (55%) |
| Lost to follow‐upa | 9 |
| Systemic therapy strategyb | |
| Monotherapy | |
| Doublet therapy | 6 (15%) |
| Solely targeted therapy | 31 (79%)2 (5%) |
| Unknown | 15 |
| Targeted therapyc in addition to chemotherapy | |
| No | 17 (46%)20 (54%) |
| Yes |
Patients were referred to a medical oncologist to start palliative chemotherapy, but no documentation was available on whether treatment was started.
Subgroup analysis for patients who received palliative systemic treatment and are not lost to follow‐up.
Only in case of known systemic chemotherapy.
After the non‐therapeutic laparotomy, 55% of patients received tumor directed palliative treatment, mostly doublet chemotherapy (79% of tumor directed palliative treatments), with or without targeted therapy (54% and 46%, respectively). Nine patients were lost to follow‐up; they were referred to a medical oncologist in a different hospital, but no further documentation was available on whether treatment was started (Table 2).
3.3. Outcome Measures – Postoperative Morbidity and Overall Survival
Pneumonia and wound infection were the most prevalent complications, both occurring 4 times (14% of all complications). Severe complications (CD ≥ 3) occurred in 9% of patients. Perforation and abscesses were most prevalent (both 20% of all severe complications) (Table 3).
Table 3.
Postoperative complications.
| Total (n = 108) | |
|---|---|
| n (%) | |
| No complication | 79 (73%) |
| Clavien‐Dindo grade 1–2 | 19 (18%) |
| Clavien‐Dindo grade 3–4 | 10 (9%) |
| Complications grade 3–4 | n (%) |
|---|---|
| Abscess | 2 (20%) |
| Cardiac complications | 1 (10%) |
| Gastroparesis | 1 (10%) |
| Ileus | 1 (10%) |
| Leakage | 1 (10%) |
| Perforation | 2 (20%) |
| Pneumonia | 0 (0%) |
| Wound dehiscence | 1 (10%) |
| Wound infection | 0 (0%) |
| Other complications | 1 (10%) |
Survival analysis showed a median OS of 6.5 months (95% CI 4.9–8.2) for the total study population. No significant differences in OS were present for any reason of irresectability (Figure 1). The primary tumor site was not of significant influence on median OS (Figure 2). Patients who received palliative systemic treatment after the discontinued CRS‐HIPEC had a significantly better median OS than patients who received best supportive care (Figure 3). The use of targeted therapy was not significantly associated to a higher overall survival as compared to systemic chemotherapy only (Figure 4).
Figure 1.
Overall survival (Kaplan‐Meier plot) per reason for the non‐therapeutic laparotomy.
Figure 2.
Overall survival (Kaplan‐Meier plot) per primary tumor location.
Figure 3.
Overall survival (Kaplan‐Meier plot) per postoperative treatment strategy.
Figure 4.
Overall survival (Kaplan‐Meier plot) systemic treatment strategy.
Of all patients included in this study, three eventually did undergo a CRS‐HIPEC after extensive palliative intent chemotherapy with a good response.
4. Discussion
This study assessed the outcome of patients with CPM in whom a planned CRS‐HIPEC was discontinued because of findings during surgery. In this study, it was clearly presented that patients who have a non‐therapeutic laparotomy have a more dismal prognosis than patients who are deemed eligible for CRS‐HIPEC, with a median OS of 6.5 months. Having a non‐therapeutic laparotomy may be of influence on receiving tumor‐directed palliative treatment without surgery. Thus, it could possibly further impair the prognosis of involved patients as receiving systemic treatment generally results in a more favorable outcome [17]. The most prevalent reason for a non‐therapeutic laparotomy was too extensive disease peroperatively. The reason for a non‐therapeutic laparotomy was not of a significant influence on the median OS. Receiving tumor directed palliative treatment after the non‐therapeutic laparotomy significantly improved the median OS.
A previous study by Cashin et al. showed a comparison in OS between postoperative intraperitoneal chemotherapy, CRS‐HIPEC and non‐therapeutic laparotomy. The present study found a comparable median OS to that of the study of Cashin, indicating that a non‐therapeutic laparotomy should be prevented. However, the comparison in the study by Cashin is disputable, as it would be better to compare the median OS after a non‐therapeutic laparotomy to that of patients with irresectable CPM, who receive tumor directed palliative systemic chemotherapy directly after diagnosis. A recent population‐based study shows a median OS of 12 months for this group [5].
The present study showed a significant difference in median OS between patients who received tumor directed palliative treatment after their discontinued procedure, and patients who did not (12.6 vs. 2.9 months, respectively). As results showed, only 55% of patients started any tumor directed palliative treatment after their discontinued procedure. These numbers are lower than those in existing literature, which vary from 71% to 75% for patients after a non‐therapeutic laparotomy for CPM [11, 12, 18]. Thus, almost half of all patients who were deemed fit enough to undergo CRS‐HIPEC eventually did not receive tumor directed palliative treatment. This is at least partly caused by the non‐therapeutic laparotomy, but as this study is based on retrospective data it is not possible to determine which other factors may have played a role in the decision to refrain from palliative treatment. Nonetheless it may be stated that by performing a laparotomy, the patient is exposed to a risk of serious complications, which was the case in 9% of all patients. The occurrence of complications was of negative influence on the chance of getting tumor directed palliative chemotherapy and thus on OS. Subsequently, complications negatively influence the quality of life of patients [19]. However, as the serious complication rate is only 9%, this is not the only explanation for patients not receiving subsequent palliative systemic therapy after a non‐therapeutic laparotomy. Furthermore, it may be related to high intra‐operative tumor burden and unfavorable disease biology, as well as postoperative functional decline potentially driven by less severe or non–Clavien–Dindo‐graded morbidity. These may nonetheless have delayed recovery and reduced eligibility for timely systemic treatment by reducing the overall physical condition of patients and simultaneously minimizing the window of opportunity for the start of palliative treatment. Additionally, although not all patients were chemotherapy‐naïve, prior systemic treatment exposure was limited in this cohort and therefore likely of lesser influence. Finally, patient preferences—possibly partly shaped by the psychological impact of a non‐therapeutic laparotomy and confrontation with limited treatment options—may have contributed to an early transition towards best supportive care. Regardless of the reason, patients who do not receive palliative treatment after a non‐therapeutic laparotomy have an even more dismal prognosis as a result.
In addition, a discontinued procedure may cause an inflammatory immunoreaction in the abdomen, which has shown to promote tumor growth [20, 21]. Apart from these patient‐related sidenotes, cancellation of a CRS‐HIPEC procedure is also undesirable considering financial and practical reasons. Altogether, efforts should be undertaken to further lower the amount of non‐therapeutic laparotomies.
4.1. Preoperative Workup
Diagnostics play a crucial role in the prevention of these non‐therapeutic laparotomies. However, a good preoperative work‐up remains one of the major challenges in CPM care [22]. All patients underwent a CT‐scan to determine PCI. Additionally, some patients had a Positron Emission Tomography‐scan (PET‐scan), a Magnetic Resonance Imaging‐scan (MRI‐scan), and as described a part of patients also underwent a DLS. Although previous evidence has shown that a DLS provides a safe way to decrease the risk of a discontinued CRS‐HIPEC, it does leave several regions of the peritoneal cavity unexamined [23, 24, 25]. Moreover, the procedure is prone for variations due to patient factors (previous surgery) and surgeons' factors (competence to expose all regions). This is supported by the present study, as almost half of patients with a discontinued CRS‐HIPEC did undergo a diagnostic laparoscopy or laparotomy (n = 48; 44%). Thus, although DLS is currently the gold standard and has proven to be of added value in the prevention of a discontinued CRS‐HIPEC [26], a non‐therapeutic laparotomy may still occur despite the performance of a DLS during preoperative work‐up. Be that as it may, the current study does not contain data on patients who did undergo a DLS and were found to not be candidates for CRS‐HIPEC based on its result. Thus, these results do not contain information on the patients who have benefited from undergoing a DLS, making it not suited to draw conclusions on the usage of DLS as part of preoperative workup.
However, in order to face the challenges in preoperative workup, several developments on diagnostics are currently ongoing, like the recently finished DISCO‐trial. This prospective trial investigated the added value of diffusion‐weighted whole‐body MRI on the resectability assessment of peritoneal disease [27]. Research has shown the use of diffusion‐weighted MRI to be promising [28, 29, 30]. However, prospective results are still to be published. Another interesting option is the use of molecular imaging through the Fibroblast Activation Protein Inhibitor (FAPI) as tracer for PET‐imaging. FAP is known to be highly present in fibroblasts in peritoneal metastases, and this characteristic is used in the FAPI‐PET imaging technique. Although it is still in its infancy, FAPI‐PET tracing has shown promising results thus far [31]. Lastly, in the near future Artificial Intelligence (AI) and radiomics models may play a role in the preoperative work‐up and treatment selection. Thus far, only two studies were published on the use of AI or radiomics models in staging of peritoneal disease. These studies aimed to classify between a high and a low PCI‐score and thus on resectability of the peritoneal disease (using a PCI of 18 and 20 as cut‐off values, respectively). Both studies demonstrated good performance of the AI assessing CT‐scans, even better than that of radiologists. However, these studies existed of small sample sizes and may have been subject to bias, stressing the need for further research. Nonetheless, these developments in the use of AI and radiomics in the evaluation of extensiveness of CPM appear promising for future strategies to prevent discontinued CRS‐HIPEC procedures [32, 33].
4.2. Bidirectional Treatment
While options were limited for patients who were not eligible for CRS‐HIPEC, recently new methods of tumor directed palliative treatment have emerged. These methods are mainly focused on the treatment strategy of bidirectional treatment: administering chemotherapy both systemically and intraperitoneally, that is, directly at the place of the metastases. The intraperitoneal chemotherapy may be administered through pressurized intraperitoneal aerosol chemotherapy (PIPAC), which is used in several countries around the globe [34, 35, 36, 37] However, currently a new technique is being investigated in the Netherlands, using catheter‐based intraperitoneal treatment [38]. The phase 2 INTERACT‐II trial is currently ongoing, aiming to determine the effect of this bidirectional treatment strategy, using systemic modified FOLFOX4 and intraperitoneal irinotecan [39]. The dose of 75 mg of this intraperitoneal irinotecan has been determined during the INTERACT‐I trial, which showed that this treatment is safe, feasible and promising in regard to survival improvement [40]. Furthermore, it is deemed less invasive for patients and less demanding for healthcare as only one surgical procedure is needed, instead of a more frequent PIPAC‐procedure. However, evidence on these statements is yet to be awaited. Nonetheless, if this treatment strategy is indeed as effective as expected, this would be a better alternative for patients with borderline resectable disease than opting for a CRS‐HIPEC with the high risk of a non‐therapeutic laparotomy, as the present study shows the risk for complications and the dismal prognosis it is accompanied by.
4.3. Limitations
This study was limited by its retrospective design, making it susceptible to bias. Furthermore, no data were present on the reason for absence of palliative systemic therapy after the discontinued CRS‐HIPEC. As a result, no conclusions could be drawn on the influence of postoperative morbidity on the use of palliative systemic chemotherapy. Table 4.
Table 4.
Overall survival.
| Variable | Median OS (95% CI) | p‐value |
|---|---|---|
| Total study population | 6.5 (5.1–8.0) | |
| Primary tumor location | 0.546 | |
| Right sided | 5.7 (3.3–8.0) | |
| Left sided | 8.7 (3.3–14.2) | |
| Rectum | 8.8 (2.3–15.4) | |
| Reason non‐therapeutic laparotomy | 0.992 | |
| Extensive disease | 6.1 (5.1–7.1) | |
| Small bowel involvement | 7.0 (2.9–11.1) | |
| Anatomically irresectable | 5.7 (4.2–7.1) | |
| Systemic metastases | 11.2 (3.6–18.8) | |
| Postoperative complication | 0.322 | |
| No postoperative complication | 7.9 (5.1–10.7) | |
| Postoperative complication | 3.6 (xx–7.8) | |
| Tumor directed palliative treatment | < 0.001 | |
| No tumor directed palliative treatment | 2.9 (2.0–3.8) | |
| Tumor directed palliative treatment | 12.6 (10.1–15.1) | |
| Systemic therapy strategya | 0.457 | |
| Monotherapy | 7.0 (0.5–13.5) | |
| Doublet therapy | 12.9 (9.3–16.5) | |
| Targeted therapy only | 6.1 (xx–xx) | |
| Targeted therapya | 0.076 | |
| No targeted therapy | 8.6 (2.2–15.0) | |
| Targeted therapy used | 13.5 (10.8–16.3) |
Subgroup‐analysis within patients who received palliative treatment and in whom the given treatment was known.
5. Conclusions
Non‐therapeutic laparotomies appear to have a clear negative impact on the overall survival of patients with extensive peritoneal metastases. Efforts should be undertaken to further lower the amount of ‐therapeutic laparotomies Developments in diagnostics, such as MRI and FAPI‐PET, as well as the implementation of AI, show promising perspectives for the preoperative workup. However, further research is needed for this to be implemented.
Synopsis
Non‐therapeutic laparotomies in patients with peritoneal metastases from colorectal cancer scheduled for CRS and HIPEC are associated with decreased survival and should be prevented.
Heuvel T. v. d., Kesteren L. v., Nienhuijs S., et al., “The Negative Impact of a Non‐Therapeutic laparotomy in Patients With Inoperable Colorectal Peritoneal Metastases,” Journal of Surgical Oncology 133, (2026): 843–851. 10.1002/jso.70240.
Teun van den Heuvel and Lars van Kesteren contributed equally.
Jurriaan Tuynman and Ignace De Hingh contributed equally.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.