Impact of frailty on postoperative outcomes in patients receiving surgery for CRC
To our knowledge, this study was first to systematically synthesize quantitative evidence and evaluate the effects of frailty on postoperative outcomes in patients who received surgery for CRC. The results showed that frailty negatively impacted postoperative complications by ~2.35-fold. Slightly higher ORs were observed in patients receiving elective surgery. Moreover, frailty was associated with 1.91- and 6.16-fold increased risks of postoperative readmission and mortality during 12 months, whereas the effect of frailty on 30-day/ inpatient mortality reached statistical significance in patients who underwent elective surgery only.
Studies previously reported frailty was an independent factor in predicting postoperative complications, readmission and mortality in abdominal and cardiothoracic surgeries in older adults [28, 29]. Because aggressive treatment (e.g. curative surgery) contributes to dysregulation of systemic immune system, causing progressive organ damage and exacerbating decline in physiological reserve [21], identifying frail patients in elderly population is essentially crucial in decision-making and therapeutic options. Moreover, postoperative outcome(s) leading to prolonged inpatient stay incurs substantial additional costs of medical care, and at the same time leading to poorer quality of life and increased risk of emergency readmission [30].
Several mechanisms potentially explain the association between frailty and postoperative adverse outcomes in patients undergoing surgery for CRC. First, frailty characterised by vulnerability and impaired physiological preserve is accompanied by up-regulation of inflammatory and proinflammatory cytokines (e.g. interleukin (IL)-6, C-reaction protein (CRP), tumour necrosis factor (TNF)-α, etc.), leading to the development of systemic inflammatory response [31]. This positive association between inflammatory markers and postoperative complications are particularly evident in occurrence of sepsis, anastomotic leakage and pulmonary insufficiency [32].
Second, frailty is frequently accompanied by the coexistence of multi-morbidity, being more frequent with increasing degrees of frailty [33]. However, while preoperative comorbidities and ASA classification are widely accepted as perioperative risk stratification tools and associated with higher risks of complications and mortality [34], the predictive value of frailty assessment instruments in conjunction with co-morbidity or perioperative complications on mortality is still limited in literature [35].
Third, increased risks of anemia, hypoalbuminemia and poor nutritional status associated with frailty have been well documented [36-38]. Condition of being anemic or malnourished directly prolonged postoperative recovery due to surgical complications (e.g. dehiscence, anastomotic leakage, surgical site infection, etc.) in colorectal and other major abdominal surgeries [39-41]. Nevertheless, the risk estimate on major surgical complications(s) such as anastomotic leakage and/or abscess formation crossed the line of null effects summarized from 4 studies in this study. There are many factors thought to affect anastomotic leakage following colorectal surgery. Evidence has showed general factors (e.g. advanced age, obesity, malnutrition, corticosteroid use, etc.), local factors (e.g. vascular flow insufficiency, infection, etc.) as well as technical and experience factors (e.g. tumour location, operative modalities (i.e. laparoscopic vs. open surgery), anastomotic tension, etc.) all influence the integrity of conduit and anastomotic healing [39, 42, 43]. Subanalyses on tumour site, operation modality, etc. were not performed in this study due to data insufficiency. The association between frailty and postoperative anastomotic leakage is yet to be investigated in future studies.
Fourth, reduction in muscle mass and mitochondrial enzyme activity exacerbated by curative operation in turn activates muscle inflammation and predisposes to frailty process [44]. Although pre-habilitation training effectively reduced morbidity and mortality after intra-abdominal cancer surgery [45], its role in improving postoperative muscle strength and functional capacity is yet to be determined. Furthermore, the degree of frailty severity fluctuating over time is rarely reported in CRC patients.
Fifth, altered composition of commensal microbiota, if present, potentiates the development of frailty and bowel oncogenicity [46, 47]. Although causal evidence showing interlinks between changes in gut microbial communities, frailty process and CRC formation is scarce, long-term alteration in gut microbiota after colorectal surgery may disturb skeletal muscle protein synthesis, resulting in muscle atrophy and attenuation [48].
Frailty assessment instruments and prevalence of frailty in patients receiving surgery for CRC
Frailty generally affects 12.8% of older individuals aged ≥60 years and is more prevalent in cancer patients [49-51]. In this systematic review and meta-analysis, we reported that preoperative prevalence rate of frailty in CRC patients aged ≥65 years was 26.0% (95% CI: 16–38% ranging from 4.4–52.2%) in 9 unique studies, with a very high level of heterogeneity identified. While dozens of frailty assessment instruments are used worldwide [52], no standard frailty index is specifically validated for CRC patients in predicting postoperative prognosis. Pandit et colleagues [21] recently proposed a modified frailty index (Colon Cancer Frailty Index (CCFI) in conjunction of previously validated Canadian Study of Health and Aging Frailty Index (CSHA-FI) and two additional variables (i.e. anemia and weight loss), guiding the strategy on treatment options and complications [21, 53].
Another indicator of frailty is the cumulative deficit index, using clinical and/or laboratory variables and expressing the index as the number of abnormal variables over the total number of variables tested [54]. The predictive value of this index in evaluating complications and mortality reached ~0.70 after gastrointestinal tract surgery [55]. However, this index is more readily available for large-scale epidemiological data than in routine clinical practice. In contrast, magnitude of impairment of physiological reserve by objective/ semi-objective measures (i.e. muscle strength, gait speed, energy expenditure, etc.) is assessed in the Fried frailty phenotype. In this meta-analysis, only one study used Fried frailty phenotype [56]. More frequently, other frailty assessment instruments (e.g. Groningen Frailty Index (GFI), the John Hopkins’ Adjusted Clinical Groups (ACG) definition of frailty, etc.) with multidimensional aspects (i.e. physical, functional and psychosocial domains) are currently used in CRC researches, in line with recommendations of the International Society of Geriatric Oncology (SIOG) suggesting that geriatric assessment (GA) incorporated with some initial screening tools (e.g. G8, VES-13, etc.) be assessed in CRC patients with ≥65 years of age who are candidates for surgical procedures [57], given that increasing age coupled with coexisting medical conditions and psychosocial issues makes therapeutic decision(s) more challenging.
Limitations of the study
There are several limitations in this systematic review and meta-analysis.
First, distribution of curative and palliative purpose that was only available in three of the included studies made it unable to in particular analyze the effect of frailty on mortality and other outcomes across the subgroups. Among patients with metastatic CRC, majority of the lesions are unresectable, despite that a few of them can still be amenable to curative resection of primary tumour and metastases. Palliative surgery is mainly reserved for these patients, which confers an operative mortality rate at 6–10% [58] and postoperative morbidity between 18–47% [59]. However, some of the studies reported that no significant association was observed between tumour stage and postoperative complication(s) [17]. Moreover, in multivariable analysis, frailty status remained to be an independent prognostic indicator after adjustment for TNM stage [16]. Second, only all-cause mortality was considered as a hard endpoint in this study. Non-cancer-specific mortality has been the main form of competing risk that occurs and leads to biased results when applying survival analysis [60]. Competing risk nomograms has been established for gastrointestinal cancer diseases in the recent years in order that overall survival (OS) and cancer-specific survival (CSS) in patients with surgically resected tumours can be predicted [61, 62]. As far as we know, only two studies previously explored discrimination between physiologically fit and non-fit patients in cancer-related and non-cancer specific mortality after curative resection for CRC [63, 64]. However, neither of them predicted outcomes by utilizing formal frailty assessment instrument(s). Competing risk models including functional and nutritional factors will be critical in classifying geriatric patients according to their frailty status [63].Third, as an important confounder affecting prognosis, emergency surgery was not absolutely eliminated in this study, although we attempted to subanalyze the patients who underwent elective surgery. The positive correlation between emergent surgical presentation and postoperative mortality in elderly patients undergoing CRC surgery was confirmed in previous studies [65, 66]. Given that an emergent surgical presentation in a senior patient frequently points at a diagnosis of bowel obstruction or perforation, these two conditions often indicate an advanced stage and carry a poor prognosis [65]. Also, it is unlikely that preoperative assessment and prehabilitation training can be implemented in these patients. Fourth, frailty assessment instruments were not uniformly assessed. Some studies mostly relied on physical components, while others used multidimensional approach, culminating in large variance in prevalence of frailty. Moreover, risk estimates were extracted directly or calculated indirectly from relatively small numbers of studies. Furthermore, univariate risk estimates were used in some of the studies when multivariate appraisals were unavailable in original publications.