Which elements of a comprehensive geriatric assessment (CGA) predict post-operative complications and early mortality after colorectal cancer surgery?

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Which elements of a comprehensive geriatric assessment (CGA) predict post-operative complications and early mortality after colorectal cancer surgery?☆ Siri R. Kristjansson a,⁎, Marit S. Jordhøy b,c , Arild Nesbakken d , Eva Skovlund e , Arne Bakka f , Hans-Olaf Johannessen g , Torgeir B. Wyller a a

University of Oslo, Department of Geriatric Medicine, Oslo University Hospital-Ullevål, 0407 Oslo, Norway Department of Internal Medicine, Innlandet Hospital Trust Gjøvik, 2819 Gjøvik, Norway c Regional Center of Excellence in Palliative Care, South-East Norway, Oslo University Hospital, Norway d University of Oslo, Surgical Department, Oslo University Hospital-Aker, 0514 Oslo, Norway e University of Oslo, School of Pharmacy, 0316 Oslo, Norway f Department of Digestive Surgery, Akershus University Hospital, University of Oslo, 1478 Lørenskog, Norway g Department of Gastrointestinal Surgery, Surgical Division, Oslo University Hospital-Ullevål, 0407 Oslo, Norway b

AR TIC LE I N FO

ABS TR ACT

Article history:

Objectives: To identify independent predictors of post-operative complications and early

Received 8 June 2010

mortality in elderly patients operated for colorectal cancer from a comprehensive geriatric

Accepted 11 June 2010

assessment [CGA] and Eastern Cooperative Oncology Group performance status [PS].

Available online 21 July 2010

Patients and Methods: Patients ≥ 70 years electively operated for all stages of colorectal cancer from 2006 to 2008 in three hospitals were consecutively included. CGA addressed the

Keywords:

following domains pre-operatively: personal and instrumental activities of daily living

Geriatric oncology

[IADL], comorbidity, polypharmacy, nutrition, cognition, and depression. The associations

Comprehensive geriatric assessment

between elements of CGA as well as PS and morbidity and mortality were analyzed using

Geriatric surgery

multivariate regression models.

Elderly

Results: Patients (182) with a median age of 80 years (range, 70–94 years) were included.

Preoperative evaluation

Severe comorbidity was an independent predictor of severe complications (odds ratio [OR]

Surgical risk

5.62; 95% CI 2.18 to 14.50) and early mortality (hazard ratio [HR] 2.78; 95% CI 1.50 to 5.17).

Colorectal cancer

IADL-dependency and depression were predictors of any complication (OR 4.02; 95% CI 1.24 to 13.09 and OR 3.68; 95% CI 0.96 to 14.08, respectively) while impaired nutrition predicted early mortality (HR 2.39, 95% CI 1.24 to 4.61). When added to the models, PS independently predicted both morbidity and early mortality, and PS was a more powerful predictor than IADL-dependency, depression, and impaired nutrition. Conclusions: In elderly patients with colorectal cancer, severe comorbidity, IADLdependency, depression, and impaired nutrition seem to be the most important CGAelements predictive of post-operative complications and early mortality. As PS predicts all outcomes, a consistent use of PS in studies of cancer surgery is recommended. © 2010 Elsevier Ltd. All rights reserved.

☆

Funding: The study is supported by a research grant from the Norwegian Cancer Society (to S.R.K.). ⁎ Corresponding author. Tel.: +47 23016137; fax: + 47 22118701. E-mail address: [email protected] (S.R. Kristjansson).

1879-4068/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jgo.2010.06.001

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Introduction In order to make the right treatment decisions for elderly patients with cancer, an approach involving a comprehensive geriatric assessment (CGA) has been advocated. Elderly patients are more likely than their younger counterparts to present with functional dependency, comorbidity, polypharmacy, malnutrition, cognitive dysfunction, and depression. It has been shown that a routine clinical evaluation including assessment of performance status does not capture the full range of problems these patients may have.1,2 However, it is poorly documented whether the additional information obtained from a CGA is of value in predicting treatment complications and survival in elderly patients undergoing cancer surgery. Studies of various surgical procedures have identified functional dependency,3 poor Eastern Cooperative Oncology Group performance status (ECOG PS),4 comorbidity,5 weight loss,6 cognitive dysfunction,7 and depression8 as independent predictors of post-operative complications. The CGA elements under investigation differed between studies, and in none a complete CGA was carried out. One exception is the multinational Preoperative Assessment of Cancer in the Elderly (PACE) study.9 This study included 460 patients over the age of 69 years with different cancer types who were assessed preoperatively in all elements of CGA except nutritional status. Dependency in instrumental activities of daily living (IADL) and moderate/severe fatigue measured by the Brief Fatigue Inventory were the only independent predictors of postoperative complications in PACE. No survival data were published. The predictive validity of CGA on survival in elderly patients operated for colorectal cancer has scarcely been studied. Papers reporting predictors of survival tend to include merely traditional variables like tumor stage, age > 70 years, tumor site, sex, extent of resection, and type of operation.10,11 In order to further explore the predictive importance of individual elements of CGA and ECOG PS in a homogeneous cohort of cancer patients, we carried out a prospective cohort study. In a previous paper, we showed that a pre-specified categorization of patients into three groups (fit, intermediate, and frail), based on a complete CGA, predicted post-operative complications, whereas advancing age and American Society of Anesthesiologists Physical Status Classification System (ASA classification) did not.12 The aim of the current paper is to investigate whether individual elements of CGA, such as functional dependency, comorbidity, polypharmacy, nutritional status, cognitive function, and depression as well as ECOG PS are independent predictors of any complication, severe complications, and/or survival in this cohort.

Patients and Methods Data Collection Procedure and Inclusion and Exclusion Criteria In Norway, all operations for colorectal cancer are performed in public hospitals. The patients in the present study were recruited from Ullevaal University Hospital, Aker University

Hospital, and Akershus University Hospital, all of which serve designated catchment areas in Oslo and Akershus County. From the routinely scheduled surgical programs at each hospital, patients were consecutively entered onto trial from November 2006 through June 2008. The Regional Committee for Medical and Health Research Ethics in East Norway approved the study. All patients aged 70 years and older who were planned for surgery of a confirmed or suspected colorectal cancer were eligible for inclusion. Ability to provide a written informed consent was mandatory. The pre-operative CGA assessment was conducted within 0 to 14 days prior to surgery. All consenting patients were interviewed at the hospital by the principal investigator, who is a medical doctor with training in geriatrics.

Information Collected Pre-operatively Comprehensive Geriatric Assessment The elements of CGA were dichotomized or categorized depending on the suggested cut-offs in the geriatric oncology literature when available, or based on cut-off criteria proposed by the authors of the tools. Functional dependence in PADL and IADL were assessed using the Barthel Index (BI) and the Nottingham Extended Activities of Daily Living Scale (NEADL).13,14 The BI assesses basic self-care abilities such as fecal continence, feeding, transferring from bed to chair and bathing/showering, while the NEADL assesses independence in mobility, kitchen, domestic and leisure activities. Maximum scores are 20 and 66, respectively, and higher scores indicate better functioning. BI scores and NEADL scores were dichotomized (<19 dependent and <44 dependent, respectively).15 Comorbidity was registered from hospital records, supplied by information from the patient interview, using the revised Cumulative Illness Rating Scale (CIRS) manual from 2008.16,17 The CIRS assesses 14 organ systems, and co-morbidity in each organ system is scored on a five-point scale ranging from grade 0 (no problem) to grade 4. Comorbidities were then classified according to CIRS-scores15,18: mild comorbidity when there was no comorbidity higher than grade 2 and less than three grade 2 comorbidities, moderate comorbidity when there were a maximum of two grade 3 comorbidities and no grade 4 comorbidities, or severe comorbidity when there were three grade 3 comorbidities or any grade 4 comorbidity. To assess nutritional, cognitive, and emotional status, we used the Mini Nutritional Assessment (MNA), Mini Mental State Examination (MMSE) and the Geriatric Depression Scale (GDS), respectively.19-21 MNA consists of 18 items including appetite, weight loss, diet, and self-perceived health, as well as anthropometric measurements. MNA scores were categorized as normal (24–30), at risk (17–23.5), or malnourished (<17).21 MMSE is a widely used screening instrument for cognitive impairment. It includes 20 items testing a variety of cognitive functions. MMSE scores were categorized as normal (27–30), intermediate (24–26), or indicative of cognitive dysfunction (<24).9 The GDS is a 30-item questionnaire that has been widely tested and used for the measurement of depression in the older population. The summary score ranges from 0 to 30, with higher scores reflecting more depressive symptoms. A score of

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14 or higher has been found to indicate depression with a sensitivity of 80% and a specificity of 100%.20 Thus, GDS-scores were dichotomized into depressed (>13) or not depressed. The number of systemic drugs in daily use was registered from the hospital records. Within the literature on drugrelated problems, the use of five or more drugs is widely used to define polypharmacy.22 Thus, polypharmacy was dichotomized (0–4 or 5+).

Eastern Cooperative Oncology Group Performance Status ECOG PS is a scale based on five levels: 0, fully active; 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light sedentary nature; 2, ambulatory and capable of all self-care, in bed less than 50% of the time; 3, capable of only limited self-care, in bed more than 50% of the time; 4, completely disabled, 100% bedridden.23 This scale is widely used in the oncology setting. The principal investigator who also did the CGA assessments scored ECOG PS.

Information Collected Post-operatively Short-term post-operative outcomes included any complication and severe complications occurring within 30 days of the surgical procedure. Complications were broadly defined as

59

any event occurring within 30 days of surgery requiring treatment measures that are not routinely applied postoperatively for colorectal cancer. To register complications, we used a predefined case report form. The data were retrospectively collected primarily from the patients' medical records, and in some cases nursing homes, rehabilitation centers, patients, or caregivers were contacted. Severity of complications was classified as minor (grade I), potentially life-threatening without (grade II) or with (grade III) lasting disability, or fatal (grade IV) based on the morbidity grading system developed by Clavien et al.24 As an example, a superficial wound infection was categorized as a grade I complication, while a wound infection requiring systemic antibiotic treatment was categorized as a grade II complication. A lower urinary tract infection was categorized as a grade I complication, while pneumonia was categorized as a grade II complication. The principal investigator in agreement with a colorectal surgeon classified all post-operative complications. Post-operative mortality was defined as death within 30 days after surgery. To assess predictors of 30-day post-operative morbidity, two dichotomized outcome variables were created; “severe” complications (grade II and higher according to the classification by Clavien et al.24) versus “no/mild complications”, and “any” complication versus “no” complications. As rectal cancer was a

Fig. 1 – Study recruitment.

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strong predictor of complications, all the analyses were corrected for tumor location. Bivariate associations between the categorical explanatory variables and the two outcome variables were assessed. CGA elements associated with the outcome with a p-value less than 0.10 were entered into a multivariable logistic regression model, and after a backward stepwise approach was applied, the final model included statistically significant variables only. ECOG PS was then entered into the final model, and backward stepwise method was applied as above. Positive predictive values for the models were defined as the percentage of cases that the models predicted to have complications that was observed to have complications. Negative predictive values were the percentage of cases predicted by the model not to have complications compared to the cases observed not to have complications. Long-term outcome was measured by cumulative survival. Information regarding patients’ deaths was retrieved from the National Registry of Norway. All deaths identified as of August 10, 2009 were included in the current analysis. Survival was defined as the number of months survived after surgery. Survival curves were calculated using the Kaplan–Meier method and compared by the log-rank test. Survival was compared between age groups (70–80 years compared to 80+), sex, according to cancer stage (grouped into stages 0–II, III, and IV), tumor location, ASA classification, Barthel index, NEADL scores, comorbidity, polypharmacy, MNA scores, MMSE scores, GDS scores, and ECOG PS. Firstly, CGA-elements and other variables bivariately associated with early mortality by the log-rank test, except for ECOG PS, were entered into a Cox proportional hazard model. The proportionality assumption was considered reasonably fulfilled, except for comorbidity and MNA scores. For this reason, comorbidity was dichotomized into mild/moderate or severe comorbidity and nutritional status was dichotomized into normal (MNA score >23.5) versus impaired in the Cox analyses. Backward elimination of non-significant variables was applied. Secondly, ECOG PS was entered into the model, and backward stepwise method was applied as above.

Results Of the 296 patients operated at the three hospitals in the inclusion period, 101 were missed for independent logistical reasons. Ten out of 195 patients approached were excluded pre-surgery; five were not able to provide consent, three refused to participate, while two were deemed unfit for surgery. Three of the 185 patients included in the study were excluded post-surgery; one did not receive a bowel resection, while two were re-operated for other reasons than complications. An overview of the recruitment is displayed in Fig. 1. The baseline characteristics are presented in Table 1. The median age was 80 years, 104 (57%) were female, 129 (71%) had colon cancer, and 22 (12%) had metastatic disease. The distributions of scores from the individual elements of CGA including ECOG PS are displayed in Table 2. The majority of patients were independent in ADL, even though 135 (74%) patients had moderate or severe comorbidity. There were no significant differences in the distribution of scores for gender or tumor location (data not shown).

Table 1 – Patient characteristics (N = 182). Characteristic

Age, years 70–74 75–79 80–84 85–89 90–94 Sex Female Male Housing Private home Institution Need for assistance Assistance from relatives or friends Public assistance Tumor location Colon Rectum Cancer stage (TNM) Stage 0 Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IIIC Stage IV Unclassified Type of surgery Open Laparoscopic Converted

Patients No.

%

43 47 58 24 10

24 26 32 13 6

104 78

57 43

177 5

97 3

47 36

26 20

129 53

71 29

8 44 56 3 5 29 11 22 4

4 24 31 2 3 16 6 12 2

120 54 8

66 30 4

Three patients died post-operatively (complication grade IV). A list of the most frequent complications is presented in Table 3. Some patients had more than one complication. Table 4 summarizes the bivariate associations between CGA–elements as well as ECOG PS and post-operative complications, corrected for tumor location. Both severe complications and any complication were strongly associated with IADL-dependency, severe comorbidity, and ECOG PS. As for the outcome any complication, there was a significant association with depression. Predictors of severe complications and any complication by multivariable logistic regression analyses are shown in Table 5. Severe comorbidity was the only CGA-element predicting severe complications (P < .001). Two CGA-elements were predictors of any post-operative complication: IADL-dependency (P = .02) and depression (P = .06). When ECOG PS was added to the models, IADL-dependency and depression were no longer independent predictors of any complication. Thus, no single CGA-element contributed to the prediction of any complication after adding ECOG PS to the model. By August 10, 2009, a total of 46 (26%) patients had died, including three post-operative deaths. Median follow-up was 20 months. The associations between patient demographics

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Table 2 – Distribution of CGA-scores and ECOG PS among the 182 patients. CGA-element Personal ADL

Instrumental ADL

Comorbidity

Polypharmacy

Nutritional status

Cognitive function

Depression

Performance status

Tool

No.

Barthel index (n = 182) Independent Dependent NEADL (n = 182) Independent Dependent CIRS (n = 182) Mild comorbidity Moderate comorbidity Severe comorbidity Number of drugs (n = 182) 0–4 5+ MNA (n = 169) Normal At risk of malnutrition Malnourished MMSE (n = 179) Good Moderately impaired Cognitive dysfunction GDS (n = 160) Not depressed Depressed ECOG PS (n = 182) ECOG 0 ECOG 1 ECOG 2 ECOG 3

%

154 28

85 15

151 31

83 17

47 94 41

26 52 23

135 47

74 26

76 77 16

45 46 9

145 22 12

81 12 7

142 18

89 11

66 62 40 14

35 34 22 8

Abbreviations: CGA, comprehensive geriatric assessment; ECOG PS, Eastern Cooperative Oncology Group performance status; ADL, acitivities of daily living; NEADL, Nottingham extended activities of daily living scale; CIRS, cumulative illness rating scale; MNA, mini nutritional assessment; MMSE, mini mental state examination; GDS, geriatric depression scale.

and clinical characteristics and overall survival are displayed in Table 6. The following variables were significantly associated with survival at the 0.10 level: sex (P = .102), cancer stage (P < .001), Table 3 – Selected post-operative complications and grading of severity. Complication

Lower urinary tract infection/ prolonged urinary retention Pulmonary (pneumonia, assisted ventilation) Cardiac (angina pectoris, myocardial infarction, arrythmia, lung oedema) Delirium Wound infection Intraabdominal abscess Anastomotic leakage Cerebrovascular accident Other

No No No Total grade grade grade I II/III IV 30

–

–

30

–

26

1

27

1

24

–

25

– 9 – – – 15

14 22 12 8 3 50

– – – 2 – –

14 31 12 10 3 65

Table 4 – Bivariate associations between elements of CGA as well as ECOG PS and severe and all complications, corrected for tumor location. CGAelement

Severe complications P

OR

1.00 1.47 0.63 to 3.40

.37

1.00 2.01 0.79 to 5.09

.14

1.00 2.84 1.24 to 6.51

.01

1.00 4.86 1.74 to 13.55

.003

1.00 1.00 1.62 0.76 to 3.46 .21 1.83 0.89 to 3.79 5.26 2.10 to 13.40 < .001 5.13 1.92 to 13.66

.10 .001

1.00 1.73 0.87 to 3.44

.12

1.00 1.67 0.82 to 3.42

.16

1.00 1.05 0.54 to 2.04 2.77 0.89 to 8.65

.88 .08

1.00 1.56 0.80 to 3.03 2.49 0.77 to 8.06

.19 .13

1.00 1.90 0.75 to 4.90 2.18 0.64 to 7.41

.18 .21

1.00 1.56 0.80 to 3.03 2.49 0.77 to 8.06

.19 .13

1.00 1.95 0.71 to 5.41

.20

4.58 1.25 to 16.84

.02

OR

Barthel index ≥ 19 < 19 NEADL scores ≥ 44 < 44 Comorbidity Mild Moderate Severe Polypharmacy 0–4 5+ MNA scores 24–30 17–23.5 < 17 MMSE scores 27–30 24–26 < 24 GDS scores ≤ 13 > 13 ECOG PS PS 0 PS 1 PS 2 PS 3

95% CI

All complications

1.00 1.49 0.70 to 3.14 3.66 1.55 to 8.64 6.62 1.79 to 24.53

95% CI

P

1.00 .30 2.46 1.17 to 5.18 .02 .003 6.05 2.39 to 15.34 <.001 <.001 6.83 1.68 to 27.77 .007

Abbreviations: CGA, comprehensive geriatric assessment; ECOG PS, Eastern Cooperative Oncology Group performance status; OR, odds ratio; CI, confidence interval; NEADL, Nottingham extended activities of daily living scale; CIRS, cumulative illness rating scale; MNA, mini nutritional assessment; MMSE, mini mental state examination; GDS, geriatric depression scale. Significant associations at the 0.10 level are in italics.

Barthel index (P = .01), NEADL scores (P = .002), comorbidity (P = .001), MNA scores (P = .094), GDS scores (P = .099), and ECOG PS (P = .001). A Cox proportional hazards model based on the significant bivariate findings was then applied, and it revealed that severe comorbidity (P = .001) and impaired nutrition (p = .009) were the CGA-elements that remained significantly correlated with early mortality (Table 7). However, when ECOG PS was added to the model, nutritional status and comorbidity were no longer independent predictors of early mortality, leaving only cancer stage and ECOG PS in the final model. In this model, patients with stage III had a hazard ratio of 2.8 for early mortality, while the hazard ratio for patients with ECOG PS 3 was 9.7. The hazard ratio for patients with stage IV disease was 12.8.

Discussion The population of elderly cancer patients is heterogeneous, and CGA is a valuable tool that systematically searches for

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Table 5 – Predictors of complications by multivariable logistic regression — final models corrected for age. Severe complications Variables Model with CGA-elements Age 70–79 80–94 Rectal cancer Comorbidity Mild Moderate Severe IADL-dependency Depression Positive predictive value Negative predictive value

OR

95% CI

1.00 .71 2.70

0.40 to 1.35 1.34 to 5.43

1.00 1.63 5.62

0.76 to 3.49 2.18 to 14.50

P

OR

95% CI

.29 .005

1.00 .99 3.27

0.50 to 1.99 1.50 to 7.11

.99 .003

P

1.24 to 13.09 0.96 to 14.08

.02 .06

0.36 to 1.41 1.61 to 7.56

.33 .002

.21 < .001 4.02 3.68 57/75 = 0.76 (76%) 48/85 = 0.56 (56%)

50/76 = 0.67 (66%) 72/106 = 0.68 (68%)

Model with CGA-elements and ECOG PS Age 70–79 1.00 80–94 .54 Rectal cancer 3.23 Comorbidity Mild 1.00 Moderate 1.39 Severe 3.41 ECOG PS PS 0 1.00 PS 1 1.37 PS 2 3.22 PS 3 4.72 Positive predictive value 51/80 = 0.64 (64%) Negative predictive value 69/102 = 0.68 (68%) Model with ECOG PS Age 70–79 80–94 Rectal cancer ECOG PS PS 0 PS 1 PS 2 PS 3 Positive predictive value Negative predictive value

Any complication

0.27 to 1.09 1.56 to 6.69

.09 .002

0.63 to 3.05 1.23 to 9.44

.42 .02

0.62 to 3.00 1.25 to 8.33 1.13 to 19.67

.44 .02 .03

1.00 .71 3.49

1.00 2.62 6.77 7.95 87/117 = 0.74 (74%) 43/65 = 0.66 (66%)

1.23 to 5.60 2.58 to 17.77 1.88 to 33.67

.01 < .001 .005

Same as above 1.00 .57 3.53 1.00 1.64 4.41 8.58 46/72 = 0.64 (64%) 72/110 = 0.65 (65%)

0.29 to 1.12 1.73 to 7.23

.10 .001

0.76 to 3.51 1.79 to 10.86 2.19 to 33.56

.21 .001 .002

Abbreviations: OR, odds ratio; CI, confidence interval; CGA, comprehensive geriatric assessment; IADL, instrumental activities of daily living; ECOG PS, Eastern Cooperative Oncology Group performance status.

remediable problems and provides an assessment of functional reserves and remaining life expectancy. In the surgical setting, CGA offers an estimate of surgical risk and identifies reversible conditions that interfere with surgery and rehabilitation.25,26 Depending on the purpose of the assessment, the importance of the individual elements of CGA is likely to differ, with some elements being more useful than others. In this study, severe comorbidity was the only CGA-element that was independently predictive of severe complications, whereas IADL-dependency and depression were independent predictors of any complication. Comorbidity and impaired nutrition were CGA-elements that independently predicted early mortality. However, in addition to being independently predictive of severe complications, ECOG PS turned out to be a stronger predictor than IADL-

dependency and depression for any complication. It was also a stronger predictor than comorbidity and impaired nutrition for early mortality. In a previous study, Repetto et al. showed that CGA adds information to ECOG PS in elderly cancer patients.1 Based on their findings, the authors suggested that ADL and IADL were more sensible than ECOG PS alone in this patient group. However, their study did not include outcome data such as treatment toxicity and survival. We found that ECOG PS was the only factor predictive of all outcomes, and more sensitive than other measures of physical ability such as PADL/IADL. Our results confirm the association between functional status and post-operative morbidity and survival reported from other studies.27-29 Previous results differ with respect to the

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Table 6 – Bivariate analyses of patient demographics and clinical characteristics and overall survival. No. of patients Variables Age, years ≥ 81 70–80 Sex Male Female Cancer stage TNM 0–II TNM III TNM IV Tumor location Colon Rectum ASA classification ASA I–II ASA III–IV Barthel index ≥ 19 < 19 NEADL scores ≥ 44 < 44 Comorbidity Mild Moderate Severe Polypharmacy 0–4 5+ MNA scores ≥ 24 17–23.5 < 17 MMSE scores 27–30 24–26 < 24 GDS scores ≥ 14 < 14 ECOG PS PS 0 PS 1 PS 2 PS 3

Died

Total

Variables P (Log-Rank Test) .516

19 27

81 101 .102

24 22

78 104 <.001

14 15 17

111 45 22 .378

35 11

129 53 .440

20 21

85 80 .010

34 12

154 28 .002

33 13

151 31 .001

10 18 18

47 94 41 .495

32 14

135 47 .094

14 24 6

76 77 16 .257

36 5 5

145 22 12

35 8

142 18

9 17 13 7

66 62 40 14

Table 7 – Predictors of early mortality by Cox regression analyses, final models.

.099

.001

Abbreviations: ASA, American Society of Anesthesiologists; NEADL, Nottingham extended activities of daily living scale; MNA, mini nutritional assessment; MMSE, mini mental state examination; GDS, geriatric depression scale; ECOG PS, Eastern Cooperative Oncology Group performance status.

most useful measurement of functional performance.4,7,9,30 One advantage of ADL assessments over ECOG PS is that they identify specific problem areas relevant for adherence to therapeutic programs, discharge planning, and rehabilitation. For prediction of treatment toxicity and survival, however, ECOG PS seems to be of great value even in elderly cancer patients. The supplementary value of PADL and IADL measures for this purpose needs to be further explored. In this study, the same person who did the CGA assessments scored

Model with CGA-elements Age 70–79 80–94 Cancer stage TNM 0, I, and II TNM III TNM IV Comorbidity Mild and moderate Severe Nutritional status Normal At risk of malnutrition/malnourished

Hazard ratio

95% CI

P

1.00 .73

0.40 to 1.36

.33

1.00 2.28 11.24

1.08 to 4.84 5.36 to 23.57

.03 < .001

1.00 2.78

1.50 to 5.17

.001

1.00 2.39

1.24 to 4.61

.009

0.33 to 1.19

.15

1.32 to 5.75 6.00 to 27.31

.007 < .001

0.94 to 4.01

.07

1.04 to 5.65 1.12 to 7.73 3.01 to 31.22

.04 .03 <.001

Model with CGA-elements and ECOG PS Age 70–79 1.00 80–94 .63 Cancer stage TNM 0, I, and II 1.00 TNM III 2.76 TNM IV 12.81 Comorbidity Mild and moderate 1.00 Severe 1.94 ECOG PS PS 0 1.00 PS 1 2.42 PS 2 2.95 PS 3 9.69

Abbreviations: CGA, comprehensive geriatric assessment; ECOG PS, Eastern Cooperative Oncology Group performance status.

ECOG PS. Thus, the basis for scoring ECOG PS was broad, and may not be directly comparable to the routine scoring of ECOG PS in a busy oncology setting. However, even when the principal investigator had extensive knowledge of the patient through a full CGA, ECOG PS provided additional information. It has previously been shown that comorbidity needs to be assessed independently from functional status.2 There are few reports on the role of comorbidity in predicting post-operative complications after surgery for colorectal cancer.3,5,9,31,32 The results are inconsistent, as are the methods for registrations of both comorbidity and complications. Only the PACE study registered comorbidity prospectively using a validated index, i.e. the Satariano's index.9 In contrast to our findings, no association between comorbidity and post-operative complications was revealed. A possible explanation is that the CIRS index used by us is more sensitive as it allows scoring of all organ systems as well as an evaluation of disease severity. Several studies in addition to ours have shown that survival of cancer patients is influenced by comorbidity.33,34 Most of these are either retrospective cohort studies, studies carried out without validated comorbidity indices, or studies where functional ability is not controlled for. A standardized comorbidity assessment in clinical trials involving elderly cancer patients

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would expand the current knowledge base and allow a more direct comparison between studies. Depression remained an independent predictor of any post-operative complication in multivariate analysis, as found by others.8,35 Depression has previously been identified as an independent predictor of post-operative delirium,36 and of adverse cardiovascular outcomes in patients with coronary heart disease.37 In PACE, there was no association between depression and post-operative morbidity. However, PACE used a short form of GDS with a low cut-off for depression. Thus, the rate of depression was 27% in PACE compared to our rate of 11%, suggesting that depression severity may influence the results. The mechanisms for the possible association between depression and morbidity need to be elucidated. Weight loss and malnutrition has been reported as risk factors for post-operative complications in patients with gastrointestinal cancer,6,38 but malnutrition was not found to be a predictor of complications in our cohort. Again the results are difficult to compare, because other studies did not correct for comorbidity and functional status. Pre-operative cognitive dysfunction is an established risk factor for post-operative delirium,39,40 and we found that patients with MMSE scores < 24 had a significantly higher rate of delirium (data not shown). However, cognitive dysfunction was neither an independent predictor of complications in general nor of early mortality. In our hospital-based study, 101 eligible patients were not assessed. These patients were randomly lost for independent logistical reasons, such as unavailability of the principal investigator, last-minute changes of the operative schedule, or pre-operative evaluations scheduled at two different hospitals at the same time. Thus, we believe that the study cohort is representative of elderly patients scheduled for surgery. For ethical reasons, nine interventions, such as referral to psychiatric follow-up, referral to dietician, and comorbidity reported to the surgeons were conducted as a direct consequence of the study. A minor impact on complication rates and overall survival cannot be entirely ruled out. The fact that assessment of patients as well as scoring of complications was performed by the same person may have caused bias. However, this person was not involved in patient treatment or surgical procedures. Even though our analyses were exploratory in nature, and need further validation in a separate cohort, the results indicate that certain elements of CGA may be more relevant than others pre-operatively. Optimizing comorbidity, nutritional support, implementation of measurements to avoid delirium in patients with pre-operative cognitive dysfunction,40 and treatment of depression are factors that may reduce complication rates. This hypothesis needs to be tested in a randomized trial. It must also be kept in mind that CGA is not merely a tool focusing on evaluating pre-operative risk, as CGA also identifies conditions that may interfere with therapeutic adherence, discharge planning, and rehabilitation. Such endpoints were not addressed in this paper.

Conclusion IADL-dependency, severe comorbidity, impaired nutrition, and depression seem to be the most important CGA-elements

associated with post-operative complications and early mortality in elderly patients electively operated for colorectal cancer. As ECOG PS is an independent predictor of all outcomes, we recommend a consistent use of ECOG PS to describe the patient population in studies of cancer surgery.

Conflict of Interest Statement TBW has hold honoraria for lectures from Pfizer, Lundbeck and Roche. SRK, MSJ, AN, ES, AB, and HOJ have no conflict of interest.

Author Contribution Study design: SRK, TBW, ES, AN, HOJ, AB, MSJ Data collection: SRK Analysis and interpretation: SRK, TBW, ES, MSJ, AN Writing of manuscript: SRK Manuscript feedback: TBW, MSJ, AN, HOJ, AB, ES All the authors approved the final manuscript.

Acknowledgments The study is supported by a research grant from the Norwegian Cancer Society (to SRK). The Norwegian Cancer Society had no role in study design, data collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

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Dr. Kristjansson is a research fellow at the Department of Geriatric Medicine, Oslo University Hospital, Ullevål and at the University of Oslo. She is specializing in internal medicine and geriatric medicine. The focus of her research is the integration of a comprehensive geriatric assessment in the pre-operative evaluation of elderly cancer patients, and the identification of frailty in elderly patients.