# Abstract

 

## Purpose This randomized controlled, clinical prospective interventional trial was aimed at exploring the effect of patient empowerment on short- and long-term outcomes after major oncologic surgery in elderly cancer patients. 

## Methods This trial was performed from February 2011 to January 2014 at two tertiary medical centers in Germany. The study included patients aged 65 years and older undergoing elective surgery for gastro-intestinal, genitourinary, and thoracic cancer. The patients were randomly assigned to the intervention group, i.e. patient empowerment through information booklet and diary keeping, or to the control group, which received standard care. Randomization was done by block randomization in blocks of four in order of enrollment. The primary outcome were 1,postoperative length of hospital stay (LOS) and 2. long-term global health-related quality of life (HRQoL) one year postoperatively. HRQoL was assessed using the EORTC QLQ C30 questionnaire. Secondary outcomes encompassed postoperative stress and complications. Further objectives were the identification of predictors of LOS, and HRQoL at 12 months. 

## Results Overall 652 patients were included. The mean age was 72 ± 4.9 years, and the majority of patients were male (68.6%, n = 447). The ^median of postoperative length of stay was 9 days (IQR 7--14 day). There were no significant differences between the intervention and the control groups in postoperative LOS (p = 0.99) or global HRQoL after one year (women: p = 0.54, men: p = 0.94). While overall complications and major complications occurred in 74% and 24% of the cases, respectively, frequency and severity of complications did not differ significantly between the groups. Patients in the intervention group reported significantly less postoperative pain (p = 0.03) than the control group. Independent predictors for LOS were identified as severity of surgery, length of anesthesia, major postoperative complications, nutritional state, and pre-operative physical functional capacity measured by the Timed Up and Go-test by multiple robust regressions. 

## Conclusion Patient empowerment through information booklet and diary keeping did not shorten the postoperative LOS in elderly onco-surgical patients, but improved quality of care regarding postoperative pain. Postoperative length of stay is influenced by pre-operative nutritional state, pre-operative functional impairment, severity of surgery, and length of anesthesia. 

## Trial Registration Clinicaltrials.gov. Identifier [NCT01278537](#) # Results 

## Patient recruitment The outline of patient recruitment and follow-up is shown in [Fig 1](#). The final sample consisted of 652 patients. Of these, 326 patients were assigned to the intervention-group and 326 patients were assigned to the control-group. After 12 months, questionnaires were sent to the patients. 103 patients (15.8%) had died. We received 450 questionnaires out of 549 (79%). Loss to follow-up was 15.2% (n = 99) after 12 months. Follow-up after 3 months was of no concern for the primary endpoints and is not considered in this analysis. 

## Baseline characteristics The socio-demographic and clinical characteristics of the patients are listed in Tables [1](#) and [2](#). The mean age of all patients was 72 ± 4.9 years. There were more men (68.6%) than women (31.4%). Distribution of tumor site is also shown in [Table 1](#). There were no differences regarding age, gender and tumor distribution between both groups (p = 0.5; p = 0.24 and p = 0.74 respectively). All other demographic and clinical data were comparable in intervention and control group ([Table 1](#)). ::::table-wrap

10.1371/journal.pone.0137824.t001

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##

##

## Demographic and clinical baseline characteristics of the study population.

:::

![](<>)

```
                                           Intervention     No Intervention   P
```

______________________________________________________________________

```
                                           N = 326          N = 326           
```

Mean Age (SD) 71.6 (4.6) 72 (5.1) 0.50[^€^](#)
Male (%) 216 (66.3%) 231 (70.9%) 0.24[^#^](#)
BMI, mean (SD) 26 (4.2) 26 (3.6) 0.49[^€^](#)
*Tumor site*\
Genito-urinary 226 (69.3%) 221 (67.8%) 0.74[^#^](#)
Abdomino-thoracic 100 (30.7%) 105 (32.2%)\
Recurrence of cancer 47 (14.4%) 44 (13.5%) 0.82[^#^](#)
*Severity of surgery*[^$^](#)\
Moderate 9 (2.8%) 9 (2.8%) 0.97[^#^](#)
Major 183 (56.1%) 186 (57.1%)\
Major+ 134 (41.1%) 131 (40.2%)\
Pre-operative Chemotherapy 40 (12.3%) 34 (10.4%) 0.54[^#^](#)
Pre-operative Radiotherapy 11 (3.4%) 16 (4.9%) 0.43[^#^](#)
ASA I/II 219 (67.2%) 206 (63.2%) 0.32[^#^](#)
ASA III/IV 107 (32.8%) 120 (36.8%)\
*Performance State ECOG*\
0 315 (96.6%) 311 (95.4%) 0.65[^#^](#)
1 8 (2.5%) 12 (3.7%)\
2/3 3 (0.9%) 3 (0.9%)\
Comorbidities [^§^](#), Median (IQR) 2 (2; 4) 2 (2; 4) 0.42[^⌘^](#)
*Nutrition state (n = 629)*[^&^](#)\
Normal 222 (70.9%) 230 (72.8%) 0.84[^#^](#)
Risk for malnutrition 83 (26.5%) 77 (24.4%)\
Malnourished 8 (2.6%) 9 (2.8%)\
*Mean hand grip strength [kg] (SD)*\
Women 23.3 (5.3) 23.1 (5.6) 0.83[^⌘^](#)
Men 39.2 (8.5) 38.9 (8.5) 0.92[^⌘^](#)
Living alone at home 64(20.8%) 62 (20.5%) >0.99[^#^](#)
Living at home with public help 16 (5.4%) 11 (3.7%) 0.33[^#^](#)
*School degree (%; n = 589)*

> High school degree 109 (37.2%) 100 (33.83%) 0.39[^#^](#)
> Surgery: median length [minutes](IQR) 165 (105; 250) 170 (105; 260) 0,42[^⌘^](#)
> Anesthesia: median length [minutes](IQR) 215 (140; 330) 220 (150; 330) 0,56[^⌘^](#)

SD = Standard deviation, BMI = Body mass index

^$^POSSUM: Physiological and Operative Severity Score for the
enUmeration of Mortality and Morbidity, IQR = Interquartile Range, MMSE
= Mini Mental State, EORTC = European Organisation of Research and
Treatment of Cancer, ASA = American Society of Anesthesiologists, ECOG
=: Eastern Cooperative Oncology Group

^§^ CCS = Charlson Comorbidity Score

^&^ Mini Nutritional Assessment (MNA)/BMI

^€^: Students' t-test

^#^: χ2-Test (Fisher's Exact test)

^⌘^: Mann Whitney U-Test:::: ::::table-wrap
10.1371/journal.pone.0137824.t002

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##

##

## Elements of the pre-operative Comprehensive Geriatric Assessment.

:::

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```
                                          Intervention     No Intervention   P
```

______________________________________________________________________

```
                                          N = 326          N = 326           
```

ADL, Median (IQR) 100 (100; 100) 100 (100; 100) 0.95[^⌘^](#)
ADL < 100 (%) (n = 645) 58 (18.0%) 57 (17.7%) 0.99[^#^](#)
IADL, Median (IQR) 8 (8;8) 8 (8;8) 0.81[^⌘^](#)
IADL < 8 (%) 53 (16.3%) 54 (16.6%) 0.95[^#^](#)
MMSE, median (IQR) 29 (28; 30) 29 (28; 30) 0.49[^⌘^](#)
MMSE \<27 (%) 28 (8.6%) 32 (9.8%) 0.69[^#^](#)
*Fatigue (BFI) (n = 575)*\
Mild fatigue 136 (47.6%) 113 (39.1%) 0.10[^#^](#)
Moderate fatigue 53 (18.5%) 68 (23.5%)\
Severe fatigue 7 (2.4%) 14 (4.8%)\
*Depression (GDS) (n = 586)*\
No depression 256 (88.0%) 265 (89.8%) 0.51[^#^](#)
Risk for /Manifest depression 35 (12.0%) 30 (10.2%)\
*Timed up and go test (TUG) (n = 619)*\
< 10 sec 231 (74.5%) 229 (74.1%) 0.92[^#^](#)
11--20 sec 64 (20.6%) 68 (22.0%)\
21--30 sec 7 (2.3%) 6 (1.9%)

> 31 sec 8 (2.6%) 6 (1.9%)\
> TUG >10 sec 79 (25.5%) 80 (25.9%) 0.93[^#^](#)
> TUG >20 sec 15 (4.8%) 12 (3.9%) 0.70[^#^](#)
> *Risk of falls (Tinetti Score) (n = 617)*\
> High (≤18 pts.) 9 (2.9%) 12 (3.9%) 0.56[^#^](#)
> Moderate (19--23 pts.) 15 (4.8%) 20 (6.5%)\
> Low (≥24 pts.) 287 (92.3%) 274 (89.5%)

ADL = Activities of daily living, IADL = Instrumental activities of
daily living, IQR = Interquartile Range, TUG = Timed up and go, BFI =
Brief fatigue inventory, GDS = Geriatric Depression Scale, SD = Standard
Deviation.

#: χ2-Test (Fisher's Exact test)

⌘: Mann Whitney U-Test:::: Furthermore, there were no differences regarding functional and cognitive tests assessed by the geriatric assessment ([Table 2](#)). In the intervention group, 193 (59%) patients rated the empowerment package as helpful or very helpful. A narrow majority of 186 (57%) kept the diary for at least 50% of the planned days, whereas 82 (25%) patients kept the diary for less than 50% of the planned days. In 58 cases (17.8%) information about diary keeping is entirely missing. 

## Primary short-term outcome 

### Postoperative in-hospital stay [Fig 2](#) shows the postoperative in-hospital stay: Duration ranged from 0 to 139 days, with a median of 9 days (Interquartile Range, IQR: 7) for all patients. There was no significant difference between both groups (p = 0.99). <figure> 10.1371/journal.pone.0137824.g002 <p><img src="" /></p> <figcaption>Median postoperative length of in-hospital stay.<br /> <strong>(A)</strong> The median length of postoperative in-hospital stay was 9 (IQR 7) days in the intervention group and 9 (IQR 9) days in the control group (p = 0.99).</figcaption> </figure> 

## Primary long-term outcome 

### Health-Related Quality of Life at 12 month At baseline mean global health-related quality of life in the intervention group was 53.95 (95% CI 49.12--58.77) in women and 68.79 (95% CI 65.90--71.69) in men. In the control group, the global HRQoL was 50.41 (95% CI 44.88--55.93) in women and 65.37 (95% CI 62.23--68.52) in men. There were no statistical differences between the groups (woman: p = 0.294; men: p = 0.196). After 12 months, questionnaires were sent to the patients. In the intervention group, 229 questionnaires were sent back, versus 221 questionnaires in the control group. The EORTC QLQ_C30 questionnaire was completed in n = 227 in the intervention group and n = 216 in the control group. Mean global HRQoL after 12 months was 69.27 (95% CI 66.45--72.14) in the intervention group and 69.79 (95% CI 66.84--72.74) in the control group (p = 0.74) ([Fig 3](#)). The global HRQoL after 12 months of women in the intervention group was 61.07 (95% CI 55.42--66.71) compared to 63.27 (95% CI 58.28--68.25) in the control group (p = 0.54). Males in the intervention group had a mean global HRQoL after 12 months of 72.49 (CI95% 69.34--75.65) compared to 71.71 (95% CI 68.21--75.20) in the control group (p = 0.94). There was no significant difference between the global HRQoL 12 months after surgery in the intervention and in the control group (all patients: p = 0.74; women: p = 0.54, men: p = 0.94). <figure> 10.1371/journal.pone.0137824.g003 <p><img src="" /></p> <figcaption>Health-related global quality of life after 12 months for intervention and control groups.<br /> HRQoL 12 months after surgery was comparable in intervention and control groups (all patients p = 0.74).</figcaption> </figure> Compared to age and gender-adjusted reference values for the German population \[[18](#)\], men showed better global health-related quality of life than the reference population. In contrast, women quoted a lower score of global HRQoL without clinical relevance (< 5 points) ([Fig 4](#)). <figure> 10.1371/journal.pone.0137824.g004 <p><img src="" /></p> <figcaption>Course of HRQoL.<br /> Comparing the baseline and follow-up values for health-related quality of life only for patients who survived and answered the 12 months questionnaire (n = 418), there were neither clinical relevant nor statistical significant differences between baseline and 12 months for HRQoL (intervention women: p = 0.58; men: p = 0.49; control women: p = 0.16; men = 0.29). Compared to age and gender-adjusted reference values for the German population \[<a href="#">18</a>\], men showed better global health-related quality of life than the reference population with clinical relevance. In contrast, women quoted a lower score of global HRQoL but without clinical relevance.</figcaption> </figure> 

## Secondary outcomes 

### Postoperative morbidity In total, 479 (74%) patients had at least one complication within postoperative hospital stay ([Fig 5](#) and [Table 3](#)). Of these, 157 (24%) were classified as major complications according to the Clavien Scale ([Fig 5](#)). <figure> 10.1371/journal.pone.0137824.g005 <p><img src="" /></p> <figcaption>Perioperative complications.<br /> Overall complications occurred in 74% of the patients. There was no difference between intervention and control group (p = 0.79). Major (Clavien Grade III and higher) perioperative complications occurred in 24% of the patients. There was no difference between the groups (p = 0.41).</figcaption> </figure> ::::table-wrap
10.1371/journal.pone.0137824.t003

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##

##

## Short-term postoperative outcomes.

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Surgical outcomes Intervention No Intervention P

______________________________________________________________________

```
                                                   N = 326        N = 326           
```

Any complications 238(73%) 241 (73.9%) 0.86[^#^](#)
Delirium 36 (11.0%) 30 (9.2%) 0.52[^#^](#)
Other neurological complications 7 (2.1%) 8 (2.5%) 1.00[^#^](#)
Acute kidney failure, oliguria 21 (6.4%) 13 (4.0%) 0.22[^#^](#)
Infections and sepsis 51 (15.6%) 46 (14.1%) 0.66[^#^](#)
Cardiopulmonary 104 (31.9%) 97 (29.8%) 0.61[^#^](#)
Hemorrhage requiring transfusion 22 (6.7%) 8 (2.5%) ***0*.*01***[^#^](#)
Anemia requiring transfusion 53 (16.3%) 46 (14.1%) 0.45[^#^](#)
Anastomotic leakage 15 (4.6%) 11 (3.4%) 0.42[^#^](#)
Intestinal obstruction 7 (2.1%) 9 (2.8%) 0.61[^#^](#)
Wound rupture abdominal 16 (4.9%) 8 (2.5%) 0.09[^#^](#)
Postoperative pain 1st postoperative day (n = 628) 234 (75.2%) 261 (82.3%) ***0*.*03***[^#^](#)
ICU stay 132 (40.7%) 124 (38.6%) 0.63[^#^](#)
ICU stay > 1 day 93 (29.6%) 89 (28.6%) 0.79[^#^](#)
Return to the OR 36 (11%) 39 (12.0%) 0.81[^#^](#)
*Depression at discharge (GDS) n = 386*\
No depression 159 (83.2%) 161 (82.6%) 0.86[^#^](#)
Risk for depression/Manifest depression 32(16.8%) 34 (17.4%)

OR: operating room, LOS: length of hospital stay, cardiopulmonary:
respiratory insufficiency, angina, myocardial infarction, arrhythmia,
lung edema, pulmonary embolism; excluded: pneumonia; SD: standard
deviation, IQR: interquartile range.

#: χ2-Test:::: The most frequent complications were cardiopulmonary complications (30.8%), followed by anemia (15.2%) and infections (14.9%) ([Table 3](#)). Occurrence and severity of complications were comparable in both groups, although severe hemorrhage occurred significantly more often in the intervention group (6.7% vs. 2.5%; p = 0.01). Delirium screening was positive in 66 (10.1%) patients with no difference between the intervention and control group (p = 0.52). Due to postoperative complications, 75 (11.5%) patients had to return to the operating theatre. 

### Postoperative stress: Mobilization, PONV and postoperative pain Patients in the intervention group reported less pain on the first postoperative day (75.2% vs. 82.3%, p = 0.03) ([Table 3](#)). There were no differences regarding mobilization within the first 24 hours (69.2% vs. 70.4%, p = 0.73), or PONV within the first five days (52.8% vs. 56.4%, p = 0.39). Further, there was no difference in the GDS between intervention and control groups at discharge (p = 0.86). 

### Readmission The readmission rate within 90 days was slightly higher for patients in the intervention group (62/245 = 25.3% vs. 59/248 = 23.8%, p = 0.70). In-hospital length of stay at readmission was shorter than in the standard of care group without reaching statistical significance (Median LOS 6.5; IQR: 11 days vs. 10; IQR: 10 days; p = 0.22). 

### Mortality Ten patients (1.5%) died before hospital discharge. Seven of these (1.1%) died within 30 days after surgery. In the intervention group, 6 (1.8%) patients died compared to 4 (1.2%) in the control group ([Fig 6](#)). At follow-up one year after surgery, 103 patients had died (15.8%). <figure> 10.1371/journal.pone.0137824.g006 <p><img src="" /></p> <figcaption>Mortality within 30 days and within one year after surgery for intervention and control groups (p = 0.75 and p = 0.19 respectively).<br /> Within 30 days after surgery, 4 patients in the intervention and 3 patients in the control group had died (p = 0.75). One year after surgery, 45 patients in the intervention group compared to 58 patients in the control group had died (p = 0.19).</figcaption> </figure> The overall mortality did not differ significantly between the two groups (Log-Rank-test p = 0.197) ([Fig 7](#)). <figure> 10.1371/journal.pone.0137824.g007 <p><img src="" /></p> <figcaption>Kaplan Meier Estimation of Survival in intervention and control groups.<br /> Patients were followed up to one year after surgery. After 12 months 103 (15.8%) patients had died. Mortality did not differ between intervention and control groups (log rank p = 0.197).</figcaption> </figure> 

### Predictors for length of in-hospital stay The intervention was not significant in robust regression analysis for primary endpoint LOS (-0.15; 95% CI -10.5--0.76; p = 0.75), whereas the pre-operative malnutrition,a delayed Time Up and Go test, increased length of anesthesia, severity of surgery, as well as postoperative major complications had a significant influence on postoperative LOS ([S1 Table](#)). 

### Predictors for HRQoL at 12 month The intervention was not significant in multivariate analysis for primary endpoint global HRQoL (EORTC QLQ C30), whereas the pre-operative global HRQoL, CCS, ASA, MMSE, severity of surgery, as well as postoperative major complications had the most significant influence on the one-year HRQoL ([S2 Table](#)). 

### Course of HRQoL Completed baseline and 12 months follow-up EORTC QLQ C-30 questionnaires were available for 418 patients. In women, the mean difference from baseline global HRQoL to global HRoL 12 months after surgery was -2.63 ± 27 in the intervention group, and -- 6,16 ± 25 in the control group (p = 0.37). In men, the mean difference score was -0.48 ± 24 in the intervention group compared to -1.62 ± 25 in the control group (p = 0.71). Between the groups, there were no clinical or statistical significant changes. Merely the women in the control group showed a small clinical decline (5--9 points difference) \[[16](#)\]. Detailed information of clinical changes (small, moderate, large) is provided in [S1 Fig](#).


Extracted trial result:
Outcome: level of postoperative pain (binary)
Intervention: intervention group, i.e. patient empowerment through information booklet and diary keeping
Comparator: control group, which received standard care
Intervention events: 234
Intervention group size: 326
Comparator events: 261
Comparator group size: 326