Quality of Life after Rectal Cancer Resection Comparing Anterior Resection, Abdominoperineal Resection, and Complicated Cases

Introduction: Compared to abdominoperineal resection (APR), sphincter preservation using low anterior resection (AR) for rectal cancer (RC) implies the risk of impaired functional outcome and postoperative complications associated with a persistent or additionally required ostomy. The aim of our study was to compare quality of life (QoL) after AR and APR with a special separate analysis of AR patients with a stoma. Methods: QoL of 84 APR, 356 AR, and 29 AR patients with complications and an additional stoma, termed converted therapy (COT) patients, was compared with regard to groups and effect of radiotherapy (RT). All patients received rectal resection between 1998 and 2013, and 47% of the patients had RT. QoL was assessed using extended EORTC QLQ-C30 and -CR38 questionnaires. Results: Questionnaires from 57 APR, 165 AR, and 25 COT patients alive were evaluated after a median time of 4 years after surgery. Global health status was equally high in AR and APR patients (score: 67), whereas COT patients turned out with a significantly lower score of 50 (p = 0.007). Compared to APR and COT, AR patients revealed less symptoms and higher functionality, especially for physical, role, and social functioning (p < 0.001). The reduction of QoL instances was significant in the COT group and in all patients treated by RT. Conclusion: QoL after RC resection may be further improved by avoiding additionally required ostomy after AR but also RT by a better individual selection of qualified patients. Qualification parameters urgently need to be defined by prospective studies.

© 2022 S. Karger AG, Basel

Introduction

In clinical oncology, improved survival is still the main objective for therapeutic success. Several factors such as total mesorectal excision and multimodal therapeutic regimes have contributed to improved prognosis of rectal cancer (RC) patients within the last decades [1]. However, markedly increased survival expectancy due to continuing improvements of surgical techniques, earlier detection, and individualized multimodal therapies has prompted a shift of the objective from simple survival to quality of survival [2]. Today, up to 50% of long-term cancer survivors suffer from chronic gastrointestinal tract symptoms (GI) after multimodal treatment of pelvic cancers impairing their quality of life (QoL) [3]. A presumably rising number of long-term survivors may result in even more patients experiencing therapy-associated long-term adverse effects. Therefore, QoL needs to be considered as a benchmark objective as well in the future.

Abdominoperineal resection (APR) with total mesorectal excision and anterior resection (AR) are standard surgical procedures for RC. Whenever technically feasible, AR is preferred to avoid permanent colostomy. Importantly, current neoadjuvant treatment may induce local downsizing of some tumors to allow AR more frequently. However, the optimization of the resection technique enabling more often deeper AR and reducing the frequency for the need of a permanent stoma as in case of APR failed to demonstrate superiority regarding QoL [4]. This has been attributed to impaired functional outcome equalizing the potential advantages of AR. Defecation problems (DF) and diarrhea (DI), even enhanced by neoadjuvant radiation, and clustering may culminate in the low anterior resection syndrome (LARS), which demonstrated to significantly worsen QoL [5, 6].

In 10–30% of patients, surgery for RC results in a permanent ostomy, which implies adverse effects as well [7-10]. Dermatitis, hernia, prolapse, and stenosis are reported in >20% besides daily management problems like leakage, noise, and odor [11]. A negative impact on the patient’s perception of body image (BI) is obvious, and several studies reported impaired QoL for that reason [12, 13]. On the other hand, the importance of stoma-related problems (STO) may be judged differently by healthcare professionals and patients, which implies the potential for QoL improvement [14]. In fact, QoL appears to be highly dependent on the patient’s requirements and the level of expectancy throughout the treatment process and following period of his life [15].

Given the regular course of AR and APR, ostomy may be either temporary or permanent. Patients adjust themselves to these circumstances prior to surgery. However, up to 20% of AR patients experience anastomotic leakage after AR. In this case, protective ostomy might have to persist lifelong or a new stoma has to be inserted [16-19]. Stenosis and local recurrence may also interfere with the initial treatment plan. In case of major complications or recurrence, AR patients will be confronted with stoma persistence or de novo creation. One would expect substantial impairment regarding QoL in this subset of patients. However, the impact on QoL has rarely been addressed regarding these situations separately.

Neoadjuvant radio(chemo)therapy (RT) has proven to provide significantly better local tumor control and to cut local recurrence rates to half [20]. It may also enable sphincter preservation in some cases. However, RT does not improve survival, yet it is associated with drawbacks in various areas of QoL [21]. Increased DF, sexual dysfunction, emotional problems, and fatigue (FA) further compromise QoL compared to surgery alone [3, 21]. Poorer functioning and treatment-related symptoms may persist on in the long-term run [22]. Due to over-staging, at least 10% of patients do not profit from RT at all [23]. Moreover, the effect of RT on QoL in APR patients and patients with secondary stoma creation is widely unclear.

The complexity of QoL in RC patients must be addressed with respect to the variability of the treatment course. The aim of our study was to assess QoL in APR, AR, and AR patients with persistent or subsequent ostomy, termed converted therapy (COT), with or without RT using prevailing cancer-specific European Organisation of Research and Treatment of Cancer (EORTC) QLQ-C30 and -CR38 questionnaires.

Materials and Methods

Study Design

This was a questionnaire-based cross-sectional evaluation of QoL of patients who received oncologic tumor resection for RC and a small number of anal cancer (AC) at the University Clinic of Ulm, Germany. We assessed QoL using EORTC QLQ-C30 questionnaire in conjunction with QLQ-CR38 questionnaire [24-26]. The latter was preferred the QLQ-CR38 update, named QLQ-CR29, to allow for consistency and comparability regarding our previous study [27]. Scores of RC and AC patients were then compared according to the type and final state of surgery resulting in 3 different groups. The APR group comprised all patients with APR as well as Hartmann’s procedure with terminal ostomy. The AR group included all patients who received sphincter-preserving anterior rectal resection without stoma placement or complete reversal of a protective stoma. AR patients with persistent or subsequent permanent ostomy placement for any reason were assigned to the COT group and evaluated separately.

Study Participants

Patients with RC and AC treated between 1998 and 2013 were identified using our tumor documentation system (Cancer REtrieval and DOcumentation System – CREDOS 3.1). This system is used to prospectively document treatment and follow-up of all our cancer patients and allows to precisely search the database for specific groups. The terms RC (ICD-10-GM code C20), AC (ICD-10-GM code C21), AR, APR, and status alive were used. A minimum time interval of 12 months from surgery to the evaluation was mandatory to eliminate early postoperative adaption as a source of bias.

A total of 469 of 976 patients were contacted by mail including an information letter, the questionnaires, and a stamped return envelope for the questionnaires. Questionnaires were collected by our tumor documentation and follow-up secretary and blinded for the present evaluation. For each patient age, gender, time elapsed after surgery, tumor stage according to Union Internationale Contre le Cancer (UICC) staging manual version 6.0, tumor location, number harvested of lymph nodes, location of distant metastasis, and neoadjuvant/adjuvant radio/chemotherapy (RT+/RT−) were recorded from the internal electronic database. Whenever applicable, type and height of anastomosis were also documented. Informed consent was obtained from all individual participants included in the study.

General Cancer-Related and Colorectal Cancer-Specific QoL Questionnaires

General cancer-related QoL was assessed using EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 module features high reliability and validity. Its outstanding performance has been demonstrated by various international multicenter studies [23]. To determine QoL, the 30 questions included are summed into 5 functional scales (physical functioning [PF2], role functioning [RF2], emotional functioning [EF], cognitive functioning [CF], and social functioning [SF]), 9 symptom scales (FA, nausea and vomiting [NV], pain [PA], dyspnea [DY], insomnia [SL], loss of appetite [AP], constipation [CO], DI, and financial difficulties [FI]), and in the global health status (QL2).

The EORTC QLQ-CR38 module was especially designed to measure cancer-specific QoL in colorectal cancer patients. It contains 38 questions which are summarized to determine QoL by 4 functional scales (BI, future perspective [FU], sexual functioning [SX], and sexual enjoyment [SE]), 8 symptom scales (micturition problems [MI], chemotherapy side effects [CT], GI, male and female sexual problems [MSX, FSX], DF, STO, and weight loss [WL]). DF was requested only from AR and STO only from APR and COT. Additionally, we attached an extra item in terms of an open question for the total number of stools per day (68 + 1 = 69 questions) to further assess functional outcome regarding DF and DI. This was done by permission grant of EORTC who explicitly allow for adding items to the QLQ-CR38 module. According to the Rome II classification, DI was defined as >3 stools per day.

Both questionnaires refer to the status of the patient a week before he/she filled out the questionnaire. High scores in functional scales and QL2 depict a high level of functioning and QoL, whereas high scores in a symptom scale represent a high level of symptomatology/dysfunction.

Statistical Analysis

Evaluation of the questionnaires was performed as recommended by the EORTC scoring methodology [25]. The estimated average of items contributing to a scale generates a raw score which is further standardized by linear transformation into a score ranging from 1 to 100 (BI score):

Subscale items had 4 response categories (1 = not at all, 2 = little, 3 = moderate, and 4 = very much, range = 3) except for QL2 (6 categories). In case of double marking adjoining answers, the lower value was assumed.

All statistical analysis was performed using SigmaPlot 12.0. For quantitative features, minimum value, maximum value, first quartile, third quartile, and median value were generated. For qualitative features, the relative frequency was determined. Data of the 3 different patient groups APR, AR, and COT were statistically evaluated and compared using the nonparametric Kruskal-Wallis test. The Wilcox ranking test was employed to analyze paralleled subgroups APR RT+ versus APR RT−, AR RT+ versus AR RT−, and COT RT+ versus COT RT−.

Regarding the additional question for the number of stools per day, the χ2 test was used to evaluate symptomatic DI (>3 stools/day) compared to asymptomatic/constipated patients (≤3 stools/day). For all statistical analysis, the level of significance was defined 5% (p < 0.05).

Results

Evaluable Questionnaires

A total of 976 patients were identified in our database, of which 469 potentially alive patients were contacted. Fifty-seven of 84 APR patients (68%), 165 of 356 AR patients (46%), and 25 of 29 COT patients alive returned questionnaires eligible for evaluation (shown in Fig. 1). Reasons for nonevaluable questionnaires were death (n = 21; 4.5%), no response at all (n = 144; 30.7%), or return of the blank questionnaires (n = 57; 12.2%).

Characterization of Eligible Patients

A characterization of all patients with evaluable questionnaires is provided in Table 1. Median age was 72 (range, 39–89) years for the APR group, 67 (range, 37–87) years for the AR group, and 73 (range, 45–83) years for COT. The male proportion accounted for 42 (74%) in the APR, 102 (62%) in the AR, and 15 (60%) in the COT group. In the APR group, the median time interval between the date of surgery and the date of this survey was 7 years (range 1–16) compared to 4 years in AR (range, 1–10) and COT (range, 1–16) patients.

Table 1.

RC was the leading diagnosis in all 3 groups (91% APR, 91% AR, and 100% COT). Sixteen patients (7%) had AC (5% APR, 8% AR, no COT). The lower tumor margin of RC was localized at a median distance of 4 cm (range, 0–7) to the anocutaneous line in the APR group than 10 cm (range, 2–20) and 7.5 cm (range, 3.5–12) in AR and COT patients, respectively. On postoperative pathological workup, pT3 pN0 was the predominant finding in all groups. Distant metastases (M+) were present in all groups to a comparable extent (22% APR, 26% AR, and 28% COT). The frequency of UICC IV tumors in the COT group (28%) was twice as high compared to the APR and AR groups (12% and 14%, respectively).

The height of the anastomosis in AR and COT patients was recorded in 75 cases with a median value of 7 cm from the anocutaneous line (range, 2–15 cm). Anastomosis was either end-to-end (n = 51/76) or side-to-end shaped (n = 25/76) and mainly created by circular double stapling using a 27–33-cm stapling device. In only 9 cases, anastomosis was performed by hand suture. Pouch reconstruction was recorded in 23 (14%) of AR patients. Eighty-eight patients received a protective loop ileostomy along with AR.

The proportion of patients receiving RT (n = 115/247, 47%) and those without RT (n = 132/247, 53%) was almost 1:1. RT, applied as single treatment modality or in combination with chemotherapy (RCT) in multimodal treatment, was applied in 33 (58%) of APR cases, 65 (40%) of AR cases, and 17 (68%) of COT cases and except for AR predominantly by neoadjuvant intention. One patient of each group (1% APR, 2% AR, and 4% COT) received both, pre- and postoperative RT.

QoL Scores

The QL2 was equally high in AR and APR patients (score: 67), whereas COT patients turned out with a significantly lower score of 50 (p = 0.007) (shown in Table 2). Functionality was generally higher in the AR group than in the APR and COT group, especially PF2 (p < 0.001), RF2 (p < 0.001), CF (p = 0.087), and SF (p < 0.001). COT patients had the lowest scores in subscales except for EF (p = 0.076). This group also revealed the highest rate of impairment regarding symptoms. The scores for FA, PA, and SL were significantly worse compared to AR and APR (p < 0.001, p = 0.004, and p = 0.33). FI and DY affected COT and APR more often than AR patients (p < 0.001 and p = 0.011, respectively).

Table 2.

QLQ-CR38 questionnaires confirmed that functionality in the AR group was generally high. Lower scores were recorded for APR and COT patients, who showed the same median values for SX and SE. Except for BI (p < 0.001), the differences between the APR, AR, and COT groups were nonsignificant. Regarding QLQ-CR38 symptom scales, significant differences were recorded for MI and CT. For MI, the score in the AR group was 22, and in the APR and COT groups 33 (p = 0.012). Regarding CT, the score in COT patients was double of that of AR and APR (22 vs. 11; p = 0.007). Comparing DF in the AR group with STO in the APR and COT groups, AR patients showed a significantly lower level of impairment (p < 0.001). Regarding the added open question for frequency of stools, the 3 groups differed markedly from each other. AR patients had the highest frequency with a median value of 3 per day (range, 0.5–25) followed by APR with 2.0 per day (range, 0.3–5) and COT with 2.5 per day (range, 0.5–10). With 52 AR patients (31%) having >3 stools per day, the difference compared to APR (n = 3; 5%) and COT (n = 6; 24%) was strikingly obvious (p = 0.003). None of the 3 groups were affected by constipation (CO).

Effect of RT

QoL was also compared with regard to RT (shown in Fig. 2, 3). RT was of no effect on QL2 comparing the AR and APR groups, but significantly impaired the COT score, which underlines the results of the main analysis (p = 0.016). Interestingly, RT improved PF2, FA, SX, and MSX of APR patients without reaching the level of statistical significance. In contrast, RT impaired DY, DI, BI, SE, and STO in this group. In AR patients, RT decreased the scores for EF, CT, SE, DF, and FSX significantly (p < 0.05). The decline in RF2, SL, and MSX was notable. The effect of RT in COT patients was almost consistently negative. RT resulted in a significant (QL2, PF2, EF, FA, PA, DI, BI, FU, chemotherapy-related problems, GI, and STO) or at least considerable (RF2, SF, DY, SL, AP, SX, SE, and WL) decline in EORTC-C30 and -CR38 subscales. Only CF, NV, CO, MI, and FI remained unchanged (shown in Fig. 4, 5). RT did not affect the median frequency of stools in AR patients (median AR RT+: 3; median AR RT−: 3), whereas APR and COT patients tended to higher values in terms of QoL (median COT RT+: 3; median COT RT−: 1). In AR RT+ patients, however, the proportion of patients having >3 stools per day was significantly increased by 9%, which implies a higher level of impairment due to irradiation in some individuals (p = 0.035). The effect in COT RT+ patients was comparable.

Discussion/Conclusion

Main Group Analysis

The main variable of RC treatment for patients is the type of surgery needed to remove the tumor. Permanent colostomy depicts the outstanding feature of APR, and it has been spaciously assumed that the bare existence would impair QoL. Intriguingly, a Cochrane review found AR equivalent to APR in terms of QoL [3]. Schmidt et al. [28] reported an even better QoL in male APR patients <70 years of age. We found the QL2 to be equally high as for AR and APR, and this finding was independent from differences in other aspects of QoL registered by the questionnaires. Our results are confirmed by recent studies comparing QoL in AR and APR patients >1 year after surgery/stoma reversal [29, 30]. The impact of bowel dysfunction after AR resulting in LARS may affect QoL to an extent that causes critical evaluation of the preoperative decision against APR [31]. Moreover, a “response shift” might help the patient to adapt to morbidity changing the internal standards and values for a good QoL over time [32, 33]. A longitudinal study by Yau et al. [34] found an equal QL2 for patients with and without permanent colostomy. However, the authors made the point that measuring the QL2 alone was not sufficient to comprehensively assess QoL. Considering other QoL parameters, our study revealed NV, AP, CO, FU, CT, GI, and FSX to be unaffected by the type of primary surgery, which demonstrates remarkable similarities. However, APR patients experienced drawbacks in some subscales compared to AR patients, pointing out different QoL profiles in functionality and symptomatology. Some authors argued that impaired PF2 of APR patients may result from reduced overall physical performance, advanced age, and female gender [35, 36]. While age could be excluded by only marginal differences between the 2 groups, the impact of female gender appears even overvalued in consideration of a female/male ratio of 1:2.8 in the APR group. FA and SL may persist for years after radical resection of RC [37]. Both were found more frequently after APR by some authors, whereas others reported an improvement [38, 39]. MI turned out to be more frequent in APR patients than in AR patients. In contrast, Engel et al. [7] reported a higher rate of MI in AR patients. Along with our findings, other studies found MI not to be impaired by AR [40, 41]. It was argued that the hypogastric nerves were even more vulnerable due to surgical procedure of APR [40]. As APR by itself does not imply additional radicalness to anatomical structures worth preserving, our findings may be explained by oncological needs. In fact, the proportion of T4 tumors in the APR group was threefold higher than in the AR group.

Up to 90% of patients experience some degree of chronic bowel dysfunction following AR [3, 5, 42]. Intriguingly, common gastrointestinal tract problems proved insignificant in AR and APR patients. Meteorism, flatulence, abdominal PA, and buttock PA also did not show a significant difference when compared to patients receiving right hemicolectomy as well as healthy volunteers [27]. In contrast, urgency, incontinence, frequent bowel movement, and clustering, which might culminate in LARS, showed a strong correlation with QoL [5, 6]. In fact, we found AR highly prone DF. However, the score for STO in APR patients resulted even worse. Both parameters may be of significant impact on QoL, but direct comparison appears problematic [43]. At least, an individual clinical relevance of up to 25 stools per day is undisputed. With 31% of the AR patients having >3 stools per day compared to 5% of APR patients, this difference was highly obvious. On the other hand, several authors found AR patients more prone to CO compared to APR [37-40]. Since CO revealed completely unaffected in AR and APR, we cannot support this view.

Regarding BI, AR patients revealed outstanding functionality compared to APR patients. Permanent colostomy impairs physical attractiveness and increases disaffection with the own body. Although our findings are mainly supported by the recent literature, continence problems in AR patients may have an equal effect on QoL [39, 41, 44, 45]. Since leakage of stoma supply systems is inherent with stoma situations, the need for optimal placement and proper care must be stressed out. Moreover, BI is closely linked to sexual dysfunction [46]. The values for SX and MSX were most distinctive in both groups, except for FSX. Although Perez Lara et al. [45] found patients with ultralow AR even more affected than with APR, our results predominantly support the assumption of BI to be highly dependent on physical self-conception and sexual problems.

Notwithstanding the potential benefits of AR in terms of QoL, the drawbacks in case of postoperative complications can be dramatic. The COT group included oncologic and nononcologic reasons for persisting or additionally required ostomy following AR. Almost all EORTC subscales declined substantially compared to AR and APR results. Impairment of QL2, PF2, RF2, SF, FA, PA, FU, CT, NV, AP, CO, and WL appeared to be permanent due to long-term follow-up. Only in case of CF, DY, SL, FI, and MI COT was in line with APR. Surprisingly, COT was of no effect on BI, which probably links to the irreversible anatomical changes going along with APR. Overall, QoL was less affected by the type of primary surgery and more by the conditions of stoma creation. Persisting or subsequent ostomy denotes a breakdown of preoperative expectations and poses additional uncertainty to the already hazardous situation of RC patients. According to Ross et al. [41], ostomy patients had poorer scores in the most QoL parameters compared to nonostomy patients. Patients, who experienced additionally required ostomy, resulted even worse in 19 of 27 QoL scales compared to those receiving a stoma along with primary surgery regardless its persistence [41]. Due to the comparatively small number of COT patients and our pointwise retrospective measurement, the therapeutic implications for this heterogeneous group must be confirmed by further prospective studies to identify specific risk factors of COT and to allow for a better individual selection of patients suitable for AR based on objective parameters involving QoL. By now, in line with Fischer et al. [47], we support a critical evaluation of APR or a Hartmann’s procedure as appropriate alternative for AR in disputable cases.

Subgroup Analysis with Regard to RT

RT-based neoadjuvant treatment of RC has been demonstrated to reduce local recurrence rates by at least 50% and may allow for sphincter preservation in some selected cases as well [18]. However, it does not improve overall survival and the long-term effect on QoL appears to be underrated [3, 44]. According to the literature, RT has a negative impact on multiple aspects of QoL [4, 13]. In our study, DY, DI, BI, SE, and STO were significantly impaired in the APR group, which was the case for SE, FSX, DF, EF, and CT in AR patients as well. These well-documented findings of a compilation of negative RT-induced side effects are remarkable when judging on treatment modality influences (RT+ surgery vs. surgery alone) on QoL. RT was repeatedly reported to increase GI, DF, and impaired SX compared to surgery alone [13, 40, 44, 48]. LARS may increase in the long term following RT [49]. Juul et al. [6] reported a substantial worsening in 7 of 8 EORTC QLQ-C30 scales as a result of major LARS compared with none or minor LARS. We found DF worsened by nearly 10 score points due to RT, and the number of patients having >3 stools per day was increased by 9%, which can be assessed as of potential clinical relevance in AR patients [50]. Some patients may also have merged into the COT group. However, other functional scales evaluating bowel function remained unaffected. We assume that irradiated AR patients had more often deeper AR promoting LARS than those without RT, which points to surgical radicalness as another important factor for the decline in DF. The QL2 in APR patients was not affected by RT. However, it was remarkable to see RT improving PF2, FA, and SX, and decreasing MSX in APR patients, while there were no improvements in AR and COT patients following irradiation. RT did not result in any improvements in AR and COT patients. The expectations of symptoms and restraints are potentially higher in APR patients compared to AR and COT, which in turn may modulate the individual degree of distress [51]. Consistently with the main analysis, COT was associated with impaired functioning and increased symptomatology in almost all EORTC QLQ-C30 and -CR38 outcomes after RT. COT patients had markedly worse outcome for QL2, PF2, and for almost any other functional and symptom scales. The negative effect on RF2, SF, DY, SL, AP, SX, SE, and WL was remarkable. We attribute this to the general insecurity and vagueness due to conversion, which may be further stressed by RT.

Limitations of the Study

Our study is limited by the lack of a baseline assessment, the retrospective nature, and a comparatively small number of participants for subgroup analysis. Low response rates for questions relating to sexual problems also have been observed elsewhere [32, 52]. Especially, the results of the RT subgroup analysis must be cautiously interpreted, last but not least, because of the changes likely to occur over a 16-year period, i.e., in indication, intention, modalities (neoadjuvant, adjuvant, combined with chemotherapy), and application technique. Additional bias may arise from the pointwise measurement of QoL, which leaves out changes over time, and would have included the data of patients, who deceased meanwhile. Since multiple surgeons were involved over the study period, the impact of the individual radicalness on QoL remains unclear, as well. On the other hand, the presence of a COT group is a specific strength, which turned out to be critically affected in terms of QoL. Due to the limited number of patients, the heterogeneity of the COT group must be analyzed in further prospective investigations. A follow-up period of minimum of 4 years after surgery and the use of well-established QoL instruments are good arguments for the validity of our findings. Therefore, our study provides profound insight into the nature of QoL on the variable course of RC therapy.

Conclusion

We conclude that the QL2 is equally high for AR and APR patients in the regular course after rectal resection. Differences in QoL proved to be of physical, psychic, and social quality, knowledge which should be included in shared decision-making. Considering the evidence of an impressive impairment of many QoL parameters by RT, and the long-term disadvantages of an additionally required stoma, a better selection of qualified patients and a critical evaluation against the decision for deep AR with terminal ostomy are desirable. Objective parameters urgently need to be defined by prospective studies.

Statement of Ethics

This is a retrospective noninterventional study, which was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. All of the patients provided written informed consent for participation in registry, data collection, evaluation, and publication. Ethics Committee approval was not required since the study involved only retrospective data of our own patient cohort.

Conflict of Interest Statement

The authors declare that they have no conflict of interest or financial interests related to the manuscript.

Funding Sources

There was no funding source relevant to this work.

Author Contributions

Jan Scheele contributed to the design and implementation of the research, processed the data, contributed to the interpretation of results, and took the lead in writing the final manuscript. Johannes Lemke aided in the interpretation of results and contributed to the preparation of the final manuscript. Mathias Wittau aided in the interpretation of results and contributed to the preparation of the final manuscript. Silvia Sander carried out data analysis and statistics, and aided interpretation of results. Doris Henne-Bruns supervised the project. Marko Kornmann conceived the original idea, contributed to the design and implementation of the research, carried out data collection, contributed to data analysis, and aided interpretation of results and preparation of the final manuscript. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.