Predicting postoperative outcome in elderly surgical cancer patients - Biomarkers and handgrip strength as predictors of postoperative outcome in elderly

Cancer is a disease that increases in incidence with age(1). As the population
is ageing, an increasing number of elderly patients will require surgical
treatment for their oncological diagnosis. In contrast to what is generally
believed, the knowledge on factors predicting postoperative outcome and quality
of life in this elderly population is very limited. Important cognitive
postoperative complications include delirium and long term cognitive decline.
It seems that an inflammatory response to surgery plays a central role in the
development of postoperative complications, especially postoperative cognitive
decline and delirium(2-5). We do not know how often these complications occur
in this group of elderly patients and what risk factors or regulatory factors
for the development of these complications are.

Ageing is characterized by a loss of muscle mass, impaired mobility and
increased incidence of malnutrition. Low albumin levels, as a marker of
malnutrition, have been associated with morbidity and mortality in hospitalized
patients (6) and lower albumin levels are found in elderly (7) and patients
with a recent diagnosis of cancer (8). In addition, a state of low-grade
inflammation is present in elderly and cancer patients(9,10). A relationship
between cancer and nutritional status by means of anorexia and inflammation has
been postulated. Biomarkers that represent nutritional and inflammatory status
include albumin, D-dimer, CRP, Il-1β, Il-6, Il-10, Il-12 and TNF-α(5,8,11).
Furthermore, assumptions can be made on possible precipitating roles of vitamin
B12, folic acid and vitamin D deficiencies in the onset of POCD in elderly
patients(12-18). Deficiencies of vitamin B12 and folic acid in elderly are
prevalent in 10-15% and 30-35% respectively(12,19). Vitamin D deficiency
affects nearly 50% of elderly in the Netherlands(20). An even higher prevalence
of deficiencies can be expected in elderly cancer patients due to the increased
metabolic activity of tumor, catabolism or reduced food intake and less
exposure to sunlight.

An inflammatory response has also been observed accompanying loss of intestinal
barrier integrity. This has mainly been investigated in animal studies,
neonates with necrotizing enterocolitis and children undergoing non-abdominal
major surgery(21-25). An association between intestinal hypoperfusion,
resulting in enterocyte cell death and loss of tight junction integrity, and
consequently a systemic inflammatory response syndrome, multi organ failure or
other major postoperative complications have been postulated(22,23). Markers
that represent enterocyte cell death and tight junction loss respectively are
Intestinal Fatty Acid Binding Protein (I-FABP) and claudin-3.

The heterogeneity of the elderly surgical population makes it impossible to
create guidelines for the elderly patients in general. The influence of
nutritional status, muscle mass and general functioning on inflammation and
outcome in the geriatric surgical patient needs to be investigated so risk
factors or predictors of adverse outcome can be determined. Objectifying these
characteristics preoperatively will allow us to identify the frail patient at
increased risk of poor outcome and the fit elderly patient with a lower risk of
adverse outcome. As a consequence appropriate interventions can take place and
well-founded treatment decisions can be made.
Since certain biomarkers are increased in elderly and others in cancer
patients, the inflammatory response and the influence of potential preoperative
confounders on the inflammatory response and thus on the occurrence of
cognitive decline, may be more pronounced in certain populations. Hypothesized
predictors of poor postoperative outcome in the onco-geriatric surgical
population should be investigated in a control group of younger surgical
oncological patients as well to assess whether different mechanisms apply to
the occurrence of an inflammatory response in age groups.

A pilot study investigating 150 patients aged 65 years and older, undergoing
surgery for a solid malignant tumor in the operative center of the University
Medical Center of Groningen is ongoing. Interim analysis of this study showed
that roughly 15 % of elderly patients experience postoperative delirium and the
same amount of patients experience long term postoperative cognitive decline.
An inflammatory response was related to the development of postoperative
delirium and cognitive decline. Peroperative serum samples of patients
experiencing either delirium or long term cognitive decline showed a sharp
increase in Il-6 (delirium), Il-10 (delirium) and Il-12 (cognitive decline)
levels compared to patients experiencing no cognitive decline or delirium. In
aged rats, an association between Il-1β, neuroinflammation and postoperative
cognitive dysfunction has been found(3). Due to the limited sample size in this
study we were not able to assess the role of potential confounders. Based on
the results of this pilot study and the pre-clinical study performed in aged
rats further research is proposed.

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The primary objective is to study the effects of the inflammatory response to a
surgical procedure on postoperative cognitive decline in elderly cancer
patients and to compare this to the effects of the inflammatory response on
postoperative cognitive decline in a control group of younger patients (<65
years of age) undergoing surgical oncological procedures. Preoperative
inflammation level, muscle strength, nutritional status and general functioning
will be investigated as possible regulatory factors of this mechanism.
The secondary objectives are to study the association between the inflammatory
response and the secondary endpoints and investigate the influence of
postoperative cognitive and functional decline on long-term quality of life.

Observational prospective study with a 1 year follow up.

The participating patients will have to complete 6 tests and 5 questionnaires
at inclusion in the study which will take about 60 minutes in total. At
discharge or at a maximum of two weeks postoperatively 4 out of the 6 tests and
1 questionnaire will be administered again. As no relevant or reliable change
is to be expected so soon after surgery at the remaining part of the test and
questionnaires, these will not be repeated at this moment. At 3 and 12 months
postoperatively the participating patients will be asked to complete the same
set of tests and questionnaires as preoperatively. Blood and urine samples will
be taken preoperatively, peroperatively and 1 and 2 days postoperatively. The
collection of blood samples necessary for this study will be combined with the
collection of blood samples used for standard care, if possible. These blood
and urine samples or the tests they are asked to complete are not expected to
cause an extra burden or discomfort to the participating patients.
Postoperative administration of blood and urine samples are not an indication
for a prolonged admission to hospital. Patients will be tested at their place
of residence or at the hospital when this can be combined with other
appointments. No extra journey to the hospital is needed. No experimental drugs
will be used during this study.
By participating in this study, patients will contribute to the collection of
data we need to gain more knowledge on the mechanism behind postoperative
cognitive decline and on risk factors of adverse postoperative outcome in the
onco-geriatric population. This will allow us to identify the frail patient at
increased risk of poor outcome and the fit elderly with a lower risk of adverse
outcome. As a consequence, appropriate interventions can take place and
well-founded treatment decisions can be made.