The five-item modified frailty index predicts long-term outcomes in elderly patients undergoing colorectal cancer surgery

doi:10.21203/rs.3.rs-2491075/v1

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The five-item modified frailty index predicts long-term outcomes in elderly patients undergoing colorectal cancer surgery

https://doi.org/10.21203/rs.3.rs-2491075/v1

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Background. Frailty has been globally recognized as a predictor of adverse postoperative outcome. A frailty assessment using the five-factor modified frailty index (5-mFI) has recently gained traction; however, long-term outcomes are largely unknown in colorectal cancer (CRC) surgery. This study aimed to investigate whether the 5-mFI predicted long-term survival and cause of death based on severity of frailty in elderly patients with CRC surgery, as well as to determine risk factors for mortality.

Methods. 299 patients underwent CRC surgery with curative intent between January 2013 and December 2017. Patients were divided into three groups based on their 5-mFI score: group 1 (5-mFI: 0, 1; n=164) with no frailty, group 2 (5-mFI: 2; n=91) with moderate frailty, and group 3 (5-mFI≧3; n=44) with severe frailty. Clinicopathological variables including comorbidity, 5-mFI, prognostic nutrition index (PNI), operative/postoperative data, and outcome including cause of death were compared among three groups. To identify factors associated with death from CRC and non-CRC-related causes, univariate and multivariate analyses using the Cox regression model were performed.

Results. Immediate postoperativemorbidity of patients with Clavien-Dindo grades of III or greater (9.1%) in group 3 were not statistically different from that in group 1 (9.1%) or group 2 (14.3%); however, the 30-day mortality rate (4.5%) in group 3 was significantly higher. Long-term disease-free survival was similar among frailty groups, suggesting CRC surgery provides oncological benefit to patients irrespective of frailty. The 5-year survival in groups 1, 2, and 3 were 83.5%, 71.2%, and 47.9%, respectively, showing a significantly lower survival rate as frailty advances. Sixty percent of deaths in frail patients were primarily from respiratory failure and cardiovascular diseases. Multivariate analysis demonstrated that advanced age, higher 5-mFI, and longer postoperative hospital stay were risk factors for mortality unrelated to CRC. Multivariate analysis also revealed that advanced tumor stage, CEA>5 ng/ml, undifferentiated tumorand R1 resection were risk factors for CRC death.

Conclusion. The 5-mFI can be a predictor of postoperative short- and long- term outcomes and risk factors for mortality unrelated to CRC. In addition, long-term survival was shown to be negatively associated with the 5-mFI score.

five-item modified frailty index

colorectal cancer surgery

non-colorectal cancer-related death

colorectal cancer death

long-term survival

Frailty is a geriatric syndrome characterized by physiologic decline of multiple organ systems and increased vulnerability to stressors. Along with an increase in the aging population worldwide, it has recently been recognized as an important risk factor in adverse outcome of elderly patients after surgery (1). Frailty is associated with postoperative complications, higher mortality, longer hospital stays, higher readmission rates, loss of independence, and increased healthcare costs (2-5). Although it has become a tool for risk stratification in older adults undergoing surgery (6), a global standard for simple and reliable assessment of frailty has not yet been established.

In 2001, a physical phenotype model by Fried et al. (7) and an accumulating deficits model by Mitnitski et al. (8) were developed. However, both are cumbersome, complex, and time-consuming because they consist of 5-92 preoperative variables that can impact decision making immediately before surgery (7-9). Subsequently, the Canadian Study of Health and Aging (CSHA) introduced a less complex frailty index (CSHA-FI) that is composed of a more clinically practicable 70 items (10). In 2013, the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) provided a modified frail index by extracting 11 variables from the original CSHA-FI (9,11). Similar to the CSHA-FI, the 11-item modified frail index (11-mFI) was proven to be a valid predictor of postoperative morbidity and mortality (9,12-14). Most recently, the five-item modified frail index (5-mFI) using a subset of 5 variables extracted from the 11-mFI was introduced (15-17). It consists of four comorbid conditions (pulmonary disease, congestive heart failure, diabetes mellitus and hypertension) and one functional status (16-18). Like the original 11-mFI, the 5-mFI has been proven to be an acceptable predictor of outcome in various surgeries including paraesophageal hernia repair, multiorgan resections, trauma, nephrectomy, breast reconstruction, spine surgery, and complex head and neck surgery (15,16,18-23).

An increase in the aging population has resulted in the need for elderly patients to undergo colorectal cancer (CRC) surgery. Although they have been shown to face higher morbidity and reduced survival (24), the influence of frailty on long-term outcome has not been well described in the literature. We previously reported that, while long-term disease-free survival of patients over 80 years was similar to that of younger age groups, more than half died of reasons unrelated to cancer (25). In the present study, we aimed to investigate whether the severity of 5-mFI predicts short- and long-term outcome of elderly patients undergoing curative CRC surgery, including determination of cause of mortality and risk factors.

The present study originally recruited 377 patients over 60 years of age who underwent elective colorectal resection with curative intent between January 2013 and December 2017 at Saint Mary’s Hospital. Seventy-eight patients were excluded because of stage Ⅳ CRC (n=57) and emergency surgery (n=21). In total, 299 patients over 60 years of age were retrospectively selected for our analysis: 248 patients with primary colon cancer and 51 patients with rectal cancer. Informed consent was obtained from individual patients and all data was collected retrospectively. The study was approved by the institutional review board at St. Mary’s Hospital in Kurume, Japan (approval number 22-0612).

Patients were divided into three groups based on the five-item modified frailty index (5-mFI) score. Group 1 (5-mFI=0,1) was negative for frailty, group 2 (5-mFI=2) was moderately frail, and group 3 (5-mFI≧3) was severely frail. The 5-mFI was determined by four comorbid conditions and one functional variable (16,18): a history of chronic obstructive pulmonary disease, congestive heart failure within 30 days post-operation, diabetes mellitus requiring oral agents or insulin, and hypertension requiring medication, as well as functional health status before operation (independent, partially, or totally dependent). Each variable represents 1 point, for a total possible score of 5 points. A score of 2 or greater indicates frailty status (16,17). The following parameters were collected from all patients:

a. Patient characteristics: age, gender, preoperative body mass index (BMI), American Society of Anesthesiologists Physical Status (ASA-PS) score, comorbidity (cardiovascular disease, hypertension, cerebral disease, renal disease, respiratory disease, diabetes mellitus, liver disease, cancer in other organs), and blood test results (hemoglobin, albumin, carcinoembryonic antigen [CEA], and prognostic nutrition index [PNI] calculated as 10 × serum albumin [g/dl] + 0.005 × total lymphocyte count [/mm³] [26])

b. Operation data: method (open or laparoscopic), amount of blood loss, duration of operation

c. Tumor-related data: tumor location (right-sided/cecum to splenic flexure, left-sided/splenic flexure to sigmoid colon, or rectum), tumor margin status (R0/R1), tumor differentiation (well, moderate/poor, mucin), and tumor stage according to the 7th edition of the Union of International Cancer Control (UICC) (27)

d. Postoperative outcomes:

Short-term: postoperative hospital stay, morbidity defined as a Clavien-Dindo class of Ⅲ or greater (28), mortality within 30 days, mortality within one year, and use of adjuvant chemotherapy
Long-term: mortality at five years in addition to cause of death, from which overall survival and disease-free survival rates were determined. Cause of death was categorized into CRC-related and CRC-unrelated which included respiratory disease, cardiovascular disease, other primary cancer, sepsis, etc.

STATISTICS

Values were expressed as frequency and percentage. Differences in the categorical variables among the three frailty groups were analyzed using the Chi-square test or Fisher’s exact test as appropriate. The duration of hospital stay was expressed as mean ± standard deviation and was analyzed using the Kruskal-Wallis test. Overall and disease-free survival rates were analyzed with the Kaplan-Meier method using the log-rank test. Overall survival was defined as the period from the date of surgery to the date of last follow-up or death. Disease-free survival was defined as the duration from surgery to the date of CRC recurrence. The univariate analysis was performed using the Cox proportional hazards model with survival time analysis as the dependent variable. Statistically significant variables were subsequently tested by multivariate analysis to determine the association between the individual determinants and death from CRC and non-CRC-related causes, and the effect of each variable was assessed by the Hazard ratio (HR) and 95% confidence interval (95% CI). A significant P value was set at α<0.05. In the log-rank test, when comparing the three groups, all paired comparisons were adjusted for the P value in multiple testing using the Holm method (29). All statistical analyses were performed using the JMP software package (version 13.0, SAS Institute, Cary, NC, USA).

Preoperative characteristics of colorectal cancer patients

Differences in preoperative features among the three groups based on the 5-mFI score are shown in Table 1. Of the 299 patients, there were 164 patients (54.9%) in group 1, 91 patients (30.4%) in group 2, and 44 patients (14.7%) in group 3. As for 5-mFI variables, the frequency of history of chronic heart failure, hypertension, diabetes, and dependence in activities of daily living were higher in direct proportion to the 5-mFI score, while there was no significant difference in history of COPD among the three groups. An increased 5-mFI score was significantly associated with older age, higher occurrence of comorbidity, and higher ASA-PS score. There was no significant difference for gender, BMI and dysphagia before surgery, and laboratory studies revealed that there was no significant difference in PNI, hemoglobin, albumin and CEA.

Table 2 showed surgical data and tumor characteristics of CRC according to 5-mFI. There were no statistical differences in amount of blood loss or duration of operation, while laparoscopic surgery occurred less in patients as the 5-mFI score increased. Investigation for tumor-related factors revealed that while stage according to UICC classification was higher in patients with an increased 5-mFI score, there was no significant difference in tumor location, tumor differentiation, or tumor margin status among the groups. Although all patients underwent surgery with curative intent, 24 specimens revealed residual tumor cells on the tumor margin (R1) across all groups: 10 (6.1%), 10 (11.0%), and 4 (9.1%), respectively. R0 resection rates followed at 93.9%, 89.0%, and 90.9% respectively. There was no significant difference in R0 resection among the three groups.

Short-term outcome

The duration of hospital stay after surgery (mean ± standard deviation) was 19.3 ± 14.5 days in group 1, 22.6 ± 18.1 days in group 2, and 24.9 ± 24.9 days in group 3, revealing that patients in group 3 required significantly longer hospital stays compared to patients in group 1 (p = 0.047). Table 3 illustrates differences in the immediate postoperative course among 5-mFI. Immediate postoperative morbidity with a Clavien-Dindo class of III or greater in groups 1–3 were 9.1%, 14.3% and 9.1%, respectively. There was no statistical difference for immediate postoperative morbidity among the three groups; however, 30-day mortality (4.5%) in group 3 was significantly higher. Two patients in group 3 died within 30 days after surgery from heart failure and aspiration pneumonia. Adjuvant chemotherapy was administered postoperatively to patients across all groups who were eligible for treatment: 68 (41.5%), 22 (24.2%), and 8 (18.2%).

Long-term outcome

The median follow-up period was 57.3 months with a range of 0.2-114.8 months: 61.0 months in group 1, 54.8 months in group 2, and 47.4 months in group 3. During follow-up, 62 patients (20.7%) developed local or distant metastases: 20.7% in group 1, 20.9% in group 2, and 20.5% in group 3, revealing that there was no significant difference in disease-free survival among the three groups (Fig. 1). Of the 299 patients, a total of 89 patients died: 37/164 (22.6%) in group 1, 29/91 (31.9%) in group 2, and 23/44 (52.3%) in group 3. A significantly higher mortality rate was observed in group 3. When classifying cause of death, 49/89 (55.1%) were from CRC and 40/89 (44.9%) were not: 75.7% vs 24.3% in group 1, 44.8% vs 55.2% in group 2, and 36.4% vs 63.6% in group 3. A notable finding was that while 75.7% of non-frail patients (28/37 in group 1) died from CRC itself, the majority of frail patients (31/52 in groups 2 and 3, about 60%) died from causes unrelated to CRC. The two primary non-cancer causes of death were respiratory failure (29.0%) and cardiovascular disease (29.0%), with other causes such as primary cancer (12.9%), sepsis (7.1%), and others (7.1%) following. Although there was no significant difference among the three groups in disease-free survival, overall survival was significantly lower in group 3 (p < 0.001) (Table 3, Figs. 1 and 2). Survival in group 3 was found to be lower than group 2 (p = 0.021) and group 1 (p < 0.001) by multiple pairwise comparison; there was no significant difference between survival in groups 1 and 2 (p = 0.070). Five-year survival in groups 1, 2, and 3 were 83.5%, 71.2%, and 47.9%, respectively, revealing that 5-year survival in patients with frailty (groups 2 and 3: 63.4%) was significantly lower than patients without frailty (group 1: 83.5%).

Factors influencing cause of death

A univariate analysis of CRC death revealed that age, PNI, Hb, CEA, tumor margin status, UICC stage, tumor differentiation, postoperative hospital stay, morbidity, and operative blood loss were significant factors influencing cause of death. Multivariate analysis showed that UICC stage, CEA, tumor differentiation, and margin status were found to be important risk factors (Table 4). A univariate analysis of non-CRC-related death revealed that age, 5-mFI, PNI, surgical procedure, tumor location, postoperative hospital stay, morbidity, and operation time were significant factors. Age, 5-mFI score, and postoperative hospital stay were found to be significant risk factors for non-CRC-related death through multivariate analysis.

In the present study, we aimed to determine the effect of frailty on short- and long-term survival of elderly patients after CRC surgery. The 5-mFI score was significantly associated with 30-day mortality, 1-year mortality, and longer hospital stay, although there was no significant difference in 30-day morbidity among the three groups. For long-term outcome, a higher 5-mFI score was associated with lower 5-year survival. While most non-frail patients died of CRC, more than half of deaths encountered in frail patients were unrelated to cancer (primarily respiratory failure and cardiovascular disease). Advanced tumor stage, elevated CEA, presence of undifferentiated tumor, and R1 resection were identified as risk factors for CRC-related death, while advanced age, higher 5-mFI, and longer postoperative hospital stay were important risk factors for non-CRC-related deaths.

Frailty is considered a state of increased vulnerability resulting from a decline in physiological function across multiple organ systems (1). It has increasingly been recognized as a high-risk state predictive of adverse health outcomes and yet an entity separate from aging and comorbidity (30), and much research on frailty has been conducted across the world in the effort to improve comprehensive geriatric assessments in older adults with cancer (15,31,32). Various frailty predictive models have been developed since 2001, but early models are cumbersome and difficult to use (9,17). In 2013, a simple 11-item modified frailty index (11-mFI) that can easily be obtained during the history and physical examination was proven to be correlated with mortality and morbidity (9), and is used broadly in the clinical setting today (12–14). An even simpler and less time-consuming 5-mFI was developed recently, and there is robust research comparing the 5-mFI and 11-mFI in predicting postoperative outcome (15–17). A weighted Kappa statistic showed strong agreement between the 5-mFI and the 11-mFI in these studies (16,17). Dauch et al. reported the 5-mFI system was 88% comparable in predicting frailty when compared to the original 11-mFI (33). Research has proven that the 5-mFI and 11-mF have similar value in their predictive ability. Furthermore, gathering data for the 5-mFI and using it in practice is relatively easy, lending itself to clinical use in the geriatric population (15). Considering the above, we decided on the 5-mFI as the assessment tool for this study.

The trend within existing research studies on frailty and postoperative outcomes is to compare data between either two groups: patients with and without frailty (3,34,35) or three groups: no frail, pre-frail, and frail (17,18,31). Dasgupta et al. utilized the Edmonton Frail Scale, whose scores range from 0 (no frail) to 17 (very frail) in patients 70 years and older undergoing non-cardiac surgery. Their research showed that patients exceeding a score of 7 had increased complications compared to those with scores less than 4 (36). Mosquera et al. classified the 11-mFI into 4 groups consisting of no frail (0 points), mildly frail (1 point), moderately frail (2 points), and severely frail ( ≧ 3 points) in thoracoabdominal operations, and increased frailty was strongly associated with increased mortality and major complications (14). We classified patients into three groups based on severity of the 5-mFI: group 1 was non-frail (5-mFI = 0,1), group 2 was moderately frail (5-mFI = 2), and group 3 was severely frail (5-mFI ≧ 3) to investigate postoperative outcome. This 3-group categorization was expected to help refine our judgment when choosing to proceed with curative CRC surgery in patients with severe frailty.

Our study showed that patients with severe frailty had significantly poorer short-term postoperative outcomes, such as 30-day/1-year mortality and longer hospital stay. These findings were corroborated by previous researchers (4,17,37), although our study showed no significant difference in 30-day morbidity. Other research has demonstrated that frailty predicts poor postoperative outcomes including higher risk of postoperative morbidity (4,13,17,18,37), higher 30-day mortality (4,13,17,37,38), longer hospital stay (4,13,17,37), higher readmission (4,13,17,37), discharge to a facility other than home (17), and reoperation (13,17). They reported short-term outcomes but lacked long-term data.

Curative resection and adjuvant treatment is the standard treatment for CRC, but there has been some debate whether surgery with curative intent should be performed on elderly patients. Historically, elderly patients with CRC have been hesitant to undergo curative surgery due to a high morbidity and mortality, and have received less aggressive treatment or even undertreatment (39–41). More recently, due to an improvement in perioperative management and use of the laparoscopic approach, the 30-day survival rate for CRC surgery patients over 65 years dropped from 6 times as high to 3 times as high as younger age groups (25). However, long-term survival in these patients has not been well described or analyzed. In the present study, contrary to the decrease in overall survival, the 5-year disease-free survival rate was found to be similar among the 3 groups, indicating oncological benefit to patients irrespective of the degree of frailty. Our study showed that risk factors for CRC death were R1 resection, advanced tumor stage, a CEA level of > 5 ng/mL, undifferentiated tumor status and longer postoperative hospital stay, all of which were findings similar to previous reports (42–44).

Studies on the effect of frailty on long-term survival in elderly patients after CRC surgery are limited and controversial. Artiles-Armas et al. reported that frailty did not affect 5-year survival (34), while Ommundsen et al. described that 5-year survival in frail patients (24%) was significantly lower than non-frail patients (66%) (35). Our study indicated that 5-year survival in frail patients (groups 2 and 3: 63.4%) was significantly lower than non-frail patients (group 1: 83.5%). Artiles-Armas et al. and Ommundsen et al. studied patients aged over 70 years with tumors ranging from stage Ⅰ-Ⅳ. Stage Ⅳ tumors accounted for 4.7% and 11.8% of their patients, respectively. In our study, we included patients over 60 years with tumors in stages I-III and excluded emergency patients and those with tumors in stage IV. The frequency of the laparoscopic approach was 79.3% in our study and 29.2–38.9% in theirs (34,35). Lower survival in their study might be caused by fewer laparoscopic approaches, in addition to inclusion of stage Ⅳ tumors. Both studies did not determine the cause of mortality in detail.

In the present study we found that, in spite of similar disease-free survival among the groups, long-term patient survival was markedly reduced in those with higher frailty caused by non-CRC-related causes. Advanced age, 5-mFI score, and postoperative hospital stay were found to be independent risk factors for non-CRC-related mortality from respiratory failure and cardiovascular disease (25). The 5-mFI has been reported to be a preoperative predictor of postoperative outcomes after liver resection, trauma, nephrectomy, breast reconstruction, spine, bladder cancer, and complex head and neck surgeries (19–23,33,45). In the present study, an elevated 5-mFI score is shown to be an important risk factor for non-cancer-related deaths after CRC surgery. Preoperative assessment using the 5-mFI may help reliably predict both non-CRC-related death as well as postoperative complications, and preoperative identification of frailty may allow for improved decision making when selecting elderly patients undergoing CRC surgery. The 5-mFI is easy to calculate and easy to apply as a standard assessment for frailty in surgery. Multimodal prehabilitation consisting of exercise, nutrition, and counseling may improve frailty and help patients avoid postoperative complications and mortality (46,47).

The present study has several limitations. It is a retrospective study that lacks assessment of postoperative quality of life. Patients with stage IV CRC and those who underwent emergency surgery were excluded, which further reduced the relatively small sample size. In addition, advanced tumor stage is disproportionately represented in patients from group 3. Strengths of this study include the availability of detailed perioperative information on the population undergoing CRC surgery, as well as the promising long-term outcomes identified. In addition, the study highlighted the potential for preoperative evaluation to become a powerful tool in determining which elderly patients might receive the most benefit from surgery.

In conclusion, the 5-mFI can be a useful predictor of certain short-term outcomes (30-day and 1-year mortality), long-term outcomes (5-year survival), and mortality unrelated to CRC. In addition, long-term survival was shown to be negatively associated with the 5-mFI score. Appropriate preoperative assessment using the 5-mFI can be a potential tool not only for selection of elderly patients for CRC surgery itself, but also for identification of patients who may benefit from a prehabilitation program preceding surgery.

5-mFI: five-item modified frailty index, CRC: colorectal cancer, UICC: Union of International Cancer Control, BMI: body mass index, CEA: carcinoembryonic antigen, PNI: prognostic nutrition index, ASA-PS: American Society of Anesthesiologists Physical Status

The authors have no financial interests related to the material described in the article.

Conflict of Interest Statement

The authors declare no conflicts of interest concerning this article.

Acknowledgment

We would like to thank Mrs. Takiko Miyakawa, cancer registrar, of St. Mary’s Hospital for her efforts in data collection.

Authors’ contributions

All authors helped to perform the research;

TO: writing the manuscript, performing data analysis and conception and design.

YS, HN: data collection and correcting the manuscript.

KK, HK, RK, KE, TT, KS: data collection.

KK, GH, TA, MT: data analysis and interpretation.

CH: statistical analysis. The authors read and approved the final manuscript.

Funding

None.

Availability of data and materials

Not applicable

Ethics approval and consent to participate

The study was approved by the Hospital Ethics Committee (approval number: 22-0612)

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Author details

¹Department of Surgery, St. Mary’s Hospital, Kurume, Fukuoka, Japan

422 Tsubukuhonmachi, Kurume, Fukuoka 830-8543, Japan

²Department of Medical Biostatistics, St. Mary’s Hospital, Kurume, Fukuoka, Japan

422 Tsubukuhonmachi, Kurume, Fukuoka 830-8543, Japan

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Tables 1 to 4 are available in the Supplementary Files section

No competing interests reported.

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The five-item modified frailty index predicts long-term outcomes in elderly patients undergoing colorectal cancer surgery

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Abstract

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Introduction

Patients And Methods

Results

Preoperative characteristics of colorectal cancer patients

Short-term outcome

Long-term outcome

Factors influencing cause of death

Discussion

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

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