Abstract
Introduction:
Prognostic Nutritional Index (PNI) is associated with disease and overall survival in patients with cancer. We aimed to assess the relationship between PNI, frailty, and six-month postoperative survival in older patients with cancer.
Methods:
In this retrospective study, patients with cancer aged ≥75 who underwent geriatric preoperative evaluation and then proceeded with elective surgery with hospital length of stay of ≥1 day and had six-month follow-up were included. PNI is measured by preoperative [10 × albumin(gr/dl)]+[0.005 × absolute lymphocyte count (per mm3)]. Higher PNI is suggestive of better nutritional status. Frailty was assessed by geriatric assessment. PNI among patients with and without each age-related impairment was evaluated. Pearson correlation coefficient was used to assess the correlation between the number of age-related impairments and PNI. Multivariable regression analysis was used to assess the relationship between six-month mortality and PNI.
Results:
PNI ranged from 19–49 (average 40) among 1,025 patients (average age 80). Patients with impairment in Karnofsky Performance Status, falls in the past year, prolonged timed up and go test, limited social activity, significant weight loss, polypharmacy, polycomorbid conditions, depression, and dependent for basic and instrumental activities of daily living had lower PNI than fit patients. The correlation coefficient between PNI and number of aging impairments was −0.28 (p<0.001). Each unit increase in PNI was associated with 10% reduction in 6-month mortality (OR=0.90, p<0.001).
Conclusion:
PNI independent of frailty, age, American Society of Anesthesiologist Performance Scale (ASA-PS), and metastatic disease is associated with six-month postoperative mortality. Future studies should assess the interventions aimed at improving PNI and its impact on surgical outcomes.
Introduction
As the population ages, cancer is becoming more prevalent in the aging population. From 1980 to 2016, total US cancer mortality for patients 65 and over increased from 258,389 to 422,927, a rise of 63.7%1. For this reason, it is imperative that we continue to evolve and improve tools for the prevention, screening, and treatment of older patients with cancer.
Nutrition plays a substantial role in not only the development of cancer2, but also in postoperative outcomes of primary tumor resection. In this vein, the prognostic nutritional index (PNI), initially proposed by Buzby et al3 and refined by Onodera et al4, is a measure used to assess perioperative nutrition by using preoperative serum albumin and total lymphocyte count. To date, a low PNI as a proxy of subpar perioperative nutritional status has been shown to be a significant predictor of poor postoperative outcomes and increased mortality of various malignancies, including colorectal5,6, pancreatic7, breast8, and non-small cell lung cancers9. However, studies on PNI focusing primarily on the geriatric cancer surgery patient population are lacking.
Frailty, which is more common among older adults, is characterized by functional deficit, dependency on others, chronic comorbidities, immune dysregulation, chronic inflammation, lack of resistance to stressors, and perioperative mortality and morbidity10,11,12,13. We now know that frailty, as opposed to chronological age, is a strong predictor of poor oncologic surgical outcome14,15.
The gold standard of measuring frailty is by geriatric assessment (GA). The GA is composed of questionnaires to assess patient functional independence, evaluation of gait and balance, and cognitive function tests16. Studies have shown that GA as a proxy of frailty is predictive of cancer surgery outcomes14.
Up to this point, studies combining the use of GA and PNI in evaluating outcomes of cancer surgery have been lacking. Additionally, there has been limited research on the impact of pre-operative PNI focusing specifically on older patients with cancer. In this study, we will explore these variables to assess their independent associations with postoperative outcomes among older patients with cancer.
Methods
Patient Population
At Memorial Sloan Kettering Cancer Center (MSKCC), patients aged 75 or older with cancer are referred to the Geriatrics service for preoperative evaluation. During preoperative evaluation, patients complete geriatric assessment (GA) by using an electronic Rapid Fitness Assessment (eRFA)17. The eRFA is a web-based e-GA that is completed by the patients or their caregivers if patients are unable to complete it on their own. It includes twelve items that assess functional domain, social support, social activity, cognitive function, nutritional status, polypharmacy, and emotional well-being of patients (eTable 1). In addition, in order to have a complete GA, comorbid conditions are retrieved from International Classification of Diseases (ICD) ninth and tenth edition codes submitted during the first 48 hours of hospital stay associated with the elective surgery. For the purpose of this study, patients were included if they were aged 75 or older, presented to MSKCC Geriatrics service for preoperative evaluation, underwent elective surgery within the first two months of that visit, had a hospital length of stay of at least one day, and completed a six-month follow. This study received approval from the MSKCC Institutional Review Board.
Prognostic Nutritional Index (PNI):
The PNI is a simple measure used to assess patient’s nutritional status. It is calculated using the method postulated by Onodera et al: [10 × albumin(gr/dl)] + [0.005 × absolute preoperative lymphocyte count (per mm3)]4. Numerous studies have validated the use of the PNI in a surgical oncology setting. For instance, Mohri et al showed that a low PNI is associated with reduced five-year survival following colorectal cancer surgery (OR = 2.25, 95% confidence interval 1.42–3.59)6. Additionally, other trials how shown associative value of a low PNI with reduced postoperative mortality in several types of cancer5,7,8,9.
Frailty:
Based on Rockwood theory of accumulation of geriatrics deficits for defining frailty, we have developed accumulative geriatrics deficit (AGD) score which ranges from 0–13 based on twelve items related to the eRFA, and one item related to number of comorbid conditions. Previously, we have shown that the AGD score is strongly associated with six-month postoperative mortality among patients with cancer aged 75 or older.18
Overall Six-Month Mortality:
Six-month mortality was retrieved from Social Security Death Index and confirmed by chart review.
Other variables:
Age, gender, metastatic disease, operation time, hospital length of stay, and American Society of Anesthesiologist Performance Scale (ASA-PS)19. Anesthesiologists assign ASA-PS to each patient during preoperative evaluation taking into account patient’s medical condition as well as overall health status. Higher ASA-PS indicates a more serious medical condition and poorer overall health status.
Analysis
A descriptive analysis was performed on the cohort, those who died within six months after surgery, and those who did not, The difference in characteristics of those who died within six months and those who survived was assessed by chi-square for categorical variables, and assessed by paired t-test for continuous variables. The multivariate regression analysis was performed by including both PNI and AGD as independent variables and six-month mortality as a dependent variable. Moreover, we adjusted the model for variables that have shown association with postoperative mortality, namely age, metastatic disease, and ASA-PS. Moreover, paired t-test was performed to assess the average PNI among those with and without each geriatric impairment. Pearson correlation co-efficient was used to assess the association between PNI and AGD.
Results
In total, 1,025 patients were included in the study. The six-month mortality rate among this cohort was 7.3% (75 patients). Sociodemographic, preoperative GA, and surgical and cancer characteristics of patients who died within the first six months after surgery and those who survived, are listed in table 1. These 1,025 patients underwent 1,544 distinct procedures. The most common procedures were colorectal (405, 26%), head and neck (259, 17%), gynecology (244, 16%), urology (181, 12%), hepatopancreatobiliary (167, 11%), and thoracic (159, 10%). Except for cognitive function, social support, distress and fall in the past year, the rest of the GA items were significantly associated with six-month mortality. The PNI of those who survived beyond six months after surgery was significantly higher than those who died (p < 0.001) (Table 1).
Table 1:
Patient Characteristics at Baseline and at six months (stratified by mortality)
| Whole cohort 1,025 | Alive in 6 months (950, 92.7%) | Dead in 6 months (75, 7.3%) | P value | |
|---|---|---|---|---|
| Age (mean/SD) | 80.3 (4.3) | 80.2 (4.2) | 81.2 (4.9) | 0.05 |
| Male | 500 (48.8%) | 457 (48.1%) | 43 (57.3%) | 0.1 |
| Poor KPS (KPS ≤ 80) | 403 (39.4%) | 354 (37.3%) | 49 (66.2%) | <0.001 |
| ADL dependency (ADL < 14) | 528 (51.7%) | 472 (49.8%) | 56 (74.7%) | <0.001 |
| iADL dependency (iADL < 16) | 479 (46.9%) | 427 (45.1%) | 52 (69.3%) | <0.001 |
| Fall in the past year | 230 (22.5%) | 207 (21.9%) | 23 (30.7%) | 0.08 |
| Timed Up and Go ≥ 10 seconds | 338 (35.1%) | 299 (33.6%) | 39 (53.4%) | 0.001 |
| Cognitive impairment (Mini-Cog ≤ 2) | 161 (16.6%) | 151 (16.9%) | 10 (14.1%) | 0.5 |
| Poor social support (Social support score ≤ 16) | 404 (39.5%) | 375 (39.6%) | 29 (38.7%) | 0.8 |
| Limited social activity (Social activity interference score ≥ 8) | 522 (51%) | 469 (49.5%) | 53 (70.7%) | <0.001 |
| Weight loss ≥ 10 pounds | 193 (20%) | 171 (19.1%) | 22 (30.1%) | 0.02 |
| High distress level (Distress thermometer score ≥ 4 | 611 (59.7%) | 560 (59.1%) | 51 (68%) | 0.1 |
| Depression (Geriatric depression score ≥ 1) | 569 (55.8%) | 515 (54.6%) | 54 (72%) | 0.003 |
| Polypharmacy (≥ 5 medications) | 416 (44.8%) | 377 (44%) | 39 (54.2%) | 0.09 |
| Poly comorbid conditions | 548 (53.5%) | 498 (52.4%) | 50 (66.7%) | 0.01 |
| PSIV | 77 (7.6%) | 70 (7.4%) | 7 (9.5%) | |
| Prognostic Nutritional Index | 40.1 (3.6) | 40.2 (3.4) | 37.9 (4.8) | <0.001 |
| Operation time (min) | 195 (138) | 196 (138) | 177 (141) | 0.2 |
| Hospital Length of Stay | 7.2 (8.3) | 6.7 (7.1) | 13.5 (16) | <0.001 |
| Metastatic disease | 82 (8%) | 71 (7.5%) | 11 (14.7%) | 0.08 |
KPS, Karnofsky Performance Status
ADL, Activities of Daily Living
iADL, Instrumental Activities of Daily Living
ASA-PS, American Society of Anesthesiologists Performance Scale
By assessing individual GA items, we found that except for cognitive function, social support, distress and falls, patients with impairments in the rest of GA items had lower PNI than those with no impairment (Figure 1). Moreover, as the number of impairments increased, the PNI decreased significantly with a correlation coefficient of −0.28 (p<0.001) (Figure 2). This suggests a weak relationship between PNI and frailty. Multivariate regression analysis adjusting for age, hospital length of stay, ASA-PS, and metastatic disease showed that PNI, independent of frailty, was associated with six-month mortality. For each unit increase in PNI, the risk of six-month mortality decreased significantly by 10% (p<0.001) (Table 2).
Figure 1:
The average PNI among patients with and without individual GA item impairment.
*p<0.05
PNI, Prognostic Nutritional Index
GA, Geriatric Assessment
KPS, Karnofsky Performance Status
ADL, Activities of Daily Living
iADL, Instrumental Activities of Daily Living
TUG, Timed Up and Go Test
Figure 2:
The average PNI based on different AGD score.
PNI, Prognostic Nutritional Index
AGD, Accumulative Geriatric Deficit
Table 2:
Multivariate Regression Analysis on association between PNI, AGD, and six-month postoperative mortality after adjustment for age, ASA-PS, metastatic disease, and length of stay.
| OR | 95% CI | P value | |
|---|---|---|---|
| PNI | 0.90 | 0.85–0.96 | 0.002 |
| AGD | 1.18 | 1.07–1.29 | <0.001 |
| Age | 1.03 | 0.98–1.09 | 0.1 |
| ASA PS III* | 0.82 | 0.27–2.43 | 0.7 |
| ASA PS IV* | 0.58 | 0.15–2.30 | 0.4 |
| Metastatic disease** | 1.79 | 0.84–3.79 | 0.1 |
| Hospital length of stay | 1.04 | 1.02–1.06 | <0.001 |
compared to ASA PS II,
compared to non-metastatic disease.
PNI, Prognostic Nutritional Index
AGD, Accumulative Geriatrics Deficit
ASA-PS, American Society of Anesthesiologists Performance Scale
Discussion
Using retrospective analysis on a large cohort of older patients with cancer aged 75 and over, we were able to show that frailty and PNI are independent risk factors for six-month mortality following elective cancer surgery. This is the first study to display this in this age cohort. To determine the PNI, we used the method developed by Onodera et al4. This measure is easy to assess given that it only requires a quick calculation using preoperational bloodwork. To determine frailty, we used GA which has been shown in the literature to be predictive of surgical outcomes in geriatric oncology.
In our large cohort of older patients with cancer, we found that for each unit increase of PNI, there was a 10% reduction in six-month mortality amongst our patients (OR=0.90, p<0.001). This value was independent of the effects of age, frailty, and metastatic disease. This concurs with previous work showing that PNI is associated with postoperative mortality in patients with cancer,6,5,7,8,9 but creates a risk measure specifically for geriatric patients.
Furthermore, we determined that factors associated with low PNI included reduced Karnofksy performance status, history of falls in the last year, prolonged timed up and go test, limited social activity, significant weight loss, polypharmacy, polycomorbid conditions, depression, and dependency on others for basic and instrumental activities of daily living. There was a weak negative correlation between PNI and number of aging impairments in our study (−0.28, p<.001). An association between PNI and AGD is not suprising since many of the risk factors for low PNI, and thus reduced six-month mortality, overlap with numerous elements of the GA. However, the weak association and independence on multivariate regression suggest that these variables do not overlap extensively and are simply associated, a concept supported by the literature20,21. For example, a review by Bonnefoy et al explored various links between nutritional intake and the development of frailty. Their work suggests an equilibrium of nutritional intake through healthy lifestyle eating patterns may be helpful in preventing frailty in older patients, but does not eliminate the risk completely21. Hence, frailty and poor nutritional status may occur without each other and should be considered their own variable.
This study shows that preoperative nutrition and frailty have significant relationships with six-month postoperative mortality in older patients with cancer. PNI is easily calculated clinically prior to surgery using the patient labs. It should be noted that even though this study associates preoperative nutrition with six-month mortality in older patients with cancer, it does not prove that nutritional supplementation will improve outcome. There is limited evidence that preoperative nutrition can reduce complication and infection risk in patients with cancer22,23, but studies are lacking in older patients with cancer. Therefore, further research on nutritional interventions prior to geriatric cancer surgery, particularly in those with a low PNI, should be completed.
Frailty as measured by the GA takes longer to assess than PNI, leading to recurrent concern in the literature regarding the feasibility of this measure. Nonetheless, the GA is done routinely by geriatricians in clinical practice. Perhaps to make calculating the GA more practical, patients can complete functional status screening questions via paper or electronic questionnaires (such as with the eRFA above). When done via this method, a comprehensive GA can be completed with only about five to six minutes of the provider’s time16. Using newer technologies, along with collaboration between the geriatrician, oncologist, and surgical team, can lead to improved implementation of the GA measure into practice. Alternatively, various other more easily measured indices have been shown to be a good proxy for GA and should be continually explored for clinical use24,25.
There are many limitations of this study. First, this analysis was completed at a single center, a comprehensive cancer center with wide access to resources. This fact combined with higher than normal collaboration between geriatrics, oncology, and surgery at our institution could be leading to an above average level of health in our sample. Thus, our study could be underestimating the effects of frailty and nutrition on mortality in the general population. To compensate for this, similar studies should be completed in less well-equipped centers with a dissimilar demographic makeup. Second, this study combines various kinds of geriatric cancer cases and surgeries together in one analysis. This could under and overstate the effects of nutrition and frailty on certain types of cancers in older patients. To address this, further studies with a similar design should be done in various types of cancer. Third, although Onodera’s simplified PNI is easy to calculate, the simplicity of this measure opens patients up for misclassification when in inflammatory states. However, the vast amount of evidence for the PNI as a predictor of post-surgical outcome suggests this effect is minimal.
This study has many strengths. It includes one of the largest cohorts of older patients with cancer undergoing surgery. The GA measure was completed by geriatricians as a routine preoperative screen and thus, is likely unbiased. The nutritional measure was done with PNI, a well-studied and objective measure. Lastly, this is the first study in older patients with cancer to assess the effect of preoperative nutrition while simultaneously controlling for the effect of frailty, a weakly associated measure, and likely weeds out some of its potential effects on the data.
Conclusion
In this large retrospective study, PNI was shown to be associated with six-month postoperative mortality in older patients with cancer undergoing tumor resection. This effect was independent of frailty, age, ASA-PS, and metastatic disease. This work highlights the need for future studies. Studies on the benefit of improving nutritional status, and thus PNI, prior to surgery in these patients and its effect on postoperative outcomes should be conducted. Also, studies like ours should be done within other cancer types in the older adult population. This would be helpful in delineating which patients would benefit more from the aforementioned intervention.
Supplementary Material
Acknowledgments
This work was supperted by the Memorial Sloan Kettering Summer Research Fellowship Grant 5R25CA020449 and NIH/NCI Cancer Center Support Grant P30CA008748.
Footnotes
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Presentation
This study was presented at the 2019 International Society of Geriatric Oncology meeting.
Conflicts of Interest
The authors have no conflict of interest to declare.
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