Modified frailty index and systemic immune-inflammation enable biological risk stratification in geriatric colorectal cancer surgery

Abstract

The global demographic shift toward an aging population has significantly increased the incidence of colorectal cancer (CRC) among older adults. However, chronological age alone is an insufficient predictor of surgical risk and oncological outcomes. A recent study published by Qi et al in World Journal of Gastrointestinal Oncology identifies the modified frailty index and the systemic immune-inflammation index as critical indices for predicting postoperative complications and recurrence-free survival. This editorial provides an in-depth analysis of how frailty and systemic inflammation intersect to dictate the clinical trajectory of geriatric CRC patients. We discuss the biological mechanisms of immunosenescence, the impact of physiological reserve depletion, and the necessity of incorporating multidimensional indices into routine clinical practice to facilitate personalized prehabilitation and optimized perioperative care.

Key Words: Colorectal cancer; Older adults; Modified frailty index; Systemic immune-inflammation index; Biological risk stratification; Postoperative complications; Recurrence-free survival

Core Tip: Chronological age alone poorly captures operative risk in older adults with colorectal cancer. Integrating the modified frailty index with the systemic immune-inflammation index (platelet count × neutrophil count/lymphocyte count) enables biological risk stratification that better predicts postoperative complications and recurrence-free survival. This combined framework links frailty-related loss of physiological reserve with inflammaging-driven immune dysregulation, clarifying why vulnerable patients deteriorate after surgical stress and supporting individualized decisions, targeted prehabilitation, and intensified perioperative surveillance.

This editorial refers to “Relationship between preoperative modified frailty index, immune-inflammation index, and outcomes of colorectal cancer surgery in older patients” by Qi et al, 2026; https://doi.org/10.4251/wjgo.v18.i2.115224.

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INTRODUCTION

With the marked aging of the global population, the incidence of colorectal cancer (CRC) among older adults is rising year by year, posing a significant public health challenge[1,2]. Although the proportion of elderly patients is increasing, chronological age alone is inadequate as the sole standard for assessing surgical risk and predicting oncologic outcomes[3]. Traditionally, clinicians often use a patient’s chronological age to decide whether they are suitable for surgery, but this approach frequently overlooks the substantial physiological heterogeneity among older individuals[4]. A healthy 70-year-old may have greater physiological reserve and better tolerance of surgery than a 60-year-old with multiple comorbidities. Such a “one-size-fits-all” age-based assessment not only risks denying potentially beneficial surgery to older patients who are otherwise fit, but also may fail to provide adequate preoperative preparation and risk stratification for high-risk patients.

It is against this background that the recent study published in World Journal of Gastrointestinal Oncology by Qi et al[5] offers a new perspective on risk assessment for elderly CRC patients. They innovatively identified the modified frailty index (mFI) and the systemic immune-inflammation index (SII) as key predictors of postoperative complications and recurrence-free survival (RFS). The significance of their work lies in shifting risk stratification from an emphasis on chronological age toward a focus on biological-age measures that better reflect an individual’s clinical status and resilience. By examining how frailty and systemic inflammation interact to shape the clinical course of geriatric CRC patients, we can better understand the biology of immunosenescence, the consequences of depleted physiological reserve, and the imperative of integrating multidimensional indices into routine practice to enable personalized prehabilitation and optimized perioperative management. As illustrated in Figure 1, reliance on chronological age alone leads to uniform treatment decisions that overlook substantial inter-individual heterogeneity, whereas mFI and SII enable biologically informed risk stratification and personalized perioperative management.

Figure 1 Chronological-age-based decision-making vs biological-risk stratification integrating frailty and systemic inflammation. The left panel illustrates a conventional chronological-age model, in which patients of different ages receive similar treatment decisions based solely on age, thereby overlooking substantial inter-individual heterogeneity. In contrast, the right panel depicts a biological-risk model that incorporates frailty, assessed by the modified frailty index, and systemic inflammation, assessed by the systemic immune-inflammation index. By capturing variations in physiological reserve and inflammatory status among patients of the same chronological age, this integrated approach enables refined risk stratification and supports personalized perioperative strategies, including tailored monitoring, prehabilitation, and modification of surgical plans. mFI: Modified frailty index; SII: Systemic immune-inflammation index (platelet count × neutrophil count/Lymphocyte count).

FRAILTY AND SYSTEMIC INFLAMMATION: THE CORNERSTONES OF RISK ASSESSMENT IN ELDERLY CRC PATIENTS

Qi et al[5] demonstrated that preoperative mFI and SII are significantly associated with postoperative complications and RFS in elderly CRC patients. Their findings not only confirm the predictive value of these two indices, but also illuminate the complex physiological challenges elderly patients face when confronting CRC and its surgical treatment.

The mFI: Quantifying depletion of physiological reserve

Frailty is a multisystem syndrome characterized by reduced physiological reserves and diminished resistance to stressors[6]. In geriatric surgery, frailty is widely recognized as an independent predictor of adverse postoperative outcomes[7]. The mFI is a simple, feasible assessment tool that typically includes multiple domains such as number of comorbidities, functional status (e.g., need for assistance), cognitive impairment, and nutritional status[8,9]. Qi et al[5] showed that patients with higher preoperative mFI scores had significantly higher rates of postoperative complications and shorter RFS.

Among elderly CRC patients, frailty represents more than physical weakness; it reflects a state of multisystem “aging”[10]. For example, reduced cardiovascular reserve impairs tolerance to anesthetic and operative hemodynamic fluctuations[11]; diminished pulmonary function increases the risk of postoperative pulmonary infection and respiratory failure[12]; renal impairment affects drug metabolism and postoperative fluid-electrolyte balance[13]. Frailty is frequently accompanied by sarcopenia and malnutrition, which further compromise immune competence and wound healing[14]. Patients with high mFI scores therefore possess low physiological reserves, and even relatively minor surgical stress may precipitate a cascade of adverse events leading to severe complications.

The SII: Capturing the dynamic balance of host inflammation

SII, calculated from peripheral blood counts of platelets, neutrophils, and lymphocytes (SII = platelet count × neutrophil count/Lymphocyte count), is a convenient and effective index reflecting the host’s inflammatory and immune status[15-17]. In various malignancies, including CRC, elevated SII has been associated with tumor progression, metastasis, and poor prognosis[18,19]. Chronic systemic inflammation is a key driver of cancer initiation and progression. Tumor cells and their microenvironment release inflammatory mediators that activate host inflammatory responses[20]; this inflammation not only promotes tumor cell proliferation, angiogenesis, and metastasis, but may also suppress antitumor immunity, facilitating immune evasion.

In elderly CRC patients, a high SII likely indicates a more pronounced chronic inflammatory state and dysregulated immunity. Older adults commonly exhibit “inflammaging”, a chronic, low-grade systemic inflammatory state even in the absence of overt infection or autoimmune disease[21]. When inflammaging coexists with tumor-related inflammation, the patient’s capacity to tolerate physiological stress is further undermined. Elevated SII may reflect a raised neutrophil-to-lymphocyte ratio (NLR) and platelet activation, signaling potentially higher tumor burden as well as increased risks of thrombosis, immune suppression, and impaired wound healing-factors closely related to postoperative complications[19,22]. The findings by Qi et al[5] reaffirm the value of preoperative SII in predicting postoperative complications and RFS in elderly CRC patients, underscoring the importance of including this measure in preoperative assessment.

BIOLOGICAL INTERPLAY BETWEEN FRAILTY AND INFLAMMATION: A VICIOUS CYCLE

The interplay between frailty and systemic inflammation can be conceptualized as a self-reinforcing cycle (Figure 2). Frailty and systemic inflammation are interdependent processes that reinforce each other in older CRC patients, thereby amplifying vulnerability to surgical stress. This biological interplay provides the mechanistic basis for incorporating multidimensional indices into perioperative risk stratification. Such insights emphasize the necessity of incorporating biological risk factors into clinical decision-making processes for elderly CRC patients.

Figure 2 Biological interplay between frailty, inflammation, and surgical stress in geriatric colorectal cancer patients. This figure illustrates the self-reinforcing cycle between frailty and inflammation, with frailty (including sarcopenia and malnutrition) exacerbating systemic inflammation and vice versa. The interaction between immunosenescence/inflammaging (e.g., elevated interleukin-6, tumor necrosis factor-α), amplified inflammation (measured by systemic immune-inflammation index), and surgical stress creates a vicious cycle that leads to worsened postoperative outcomes, including increased risk of infection, organ failure, and delirium. Optimizing chronic disease management, minimizing surgical trauma, and addressing frailty through prehabilitation may reduce the negative clinical consequences and improve recurrence-free survival. SII: Systemic immune-inflammation index; mFI: Modified frailty index; CRP: C-reactive protein; NLR: Neutrophil-to-lymphocyte ratio; RFS: Recurrence-free survival; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α.

Immunosenescence and inflammaging: The fragile foundation of the older host

Immunosenescence refers to the age-related decline in immune system function, manifested by reduced adaptive immune responses (e.g., diminished diversity of T-cell and B-cell repertoires and poorer vaccine responses) and altered innate immunity (e.g., impaired macrophage and neutrophil function)[23]. One consequence of immunosenescence is inflammaging, a persistent, low-grade proinflammatory state[21]. Senescent cells and aging tissues release damage-associated molecular patterns that activate innate immune cells and elevate proinflammatory cytokines [such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP)][24].

In the context of CRC, immunosenescence and inflammaging make older patients more susceptible to cancer development. Tumors themselves secrete cytokines and chemokines that further amplify systemic inflammation. This chronic inflammation not only directly promotes tumor growth and metastasis, but also impairs antitumor immune responses, allowing tumor cells to escape immune surveillance.

Amplifying effects of frailty on inflammation

In frail patients, diminished physiological reserve reduces the ability to regulate inflammatory responses. Frailty commonly coexists with chronic diseases (e.g., diabetes, cardiovascular disease) that are themselves drivers of systemic inflammation. Malnutrition, which is prevalent among frail individuals-impairs immune cell production and function and can compromise gut barrier integrity, increasing bacterial translocation and systemic inflammatory load[25]. Sarcopenia, a core component of frailty, further contributes because skeletal muscle is not only a locomotive organ but also an endocrine organ that secretes myokines; muscle loss can dysregulate myokine production and worsen inflammation[26]. Thus, frail patients often exhibit more intense and persistent inflammatory responses that are harder to resolve, elevating the risk of postoperative complications.

Inflammation accelerating frailty

Conversely, chronic systemic inflammation accelerates the progression of frailty[24]. Proinflammatory cytokines promote muscle protein catabolism and inhibit protein synthesis, thereby worsening sarcopenia. Inflammatory mediators act on the nervous system to reduce appetite, induce fatigue, and impair cognition, which are core features of frailty. Chronic inflammation can also provoke endocrine disturbances (e.g., lowered testosterone, altered cortisol signaling), further altering body composition and function. Therefore, inflammation and frailty create a self-reinforcing loop: Frailty impairs inflammatory regulation and amplifies inflammation; persistent inflammation accelerates frailty progression.

In the perioperative period, surgical trauma itself is a potent inflammatory stimulus. For frail elderly CRC patients who already harbor chronic inflammation, the added inflammatory burden of surgery may exceed their limited physiological reserve, leading to serious postoperative complications such as infection, cardiopulmonary failure, and delirium, and may even affect long-term survival.

FROM CHRONOLOGICAL AGE TO BIOLOGICAL RISK STRATIFICATION: PRACTICAL IMPLICATIONS OF A PARADIGM SHIFT

Building on the biological framework outlined above, we focus here on the practical implications of applying mFI and SII for perioperative decision-making. Qi et al’s study[5] proposes more than new predictive markers; it advocates a paradigm shift in risk assessment-moving from reliance on chronological age toward biologically grounded risk stratification. This shift holds profound implications for the clinical management of elderly CRC patients. Importantly, current evidence primarily supports the prognostic and stratification value of mFI and SII; whether mFI/SII-guided interventions improve outcomes requires prospective interventional validation.

Precise preoperative assessment and risk stratification

Conventional preoperative evaluation often focuses on organ-specific function (e.g., cardiopulmonary testing) but seldom captures a patient’s holistic physiological reserve and capacity to withstand perioperative stress[3]. Combining mFI and SII offers clinicians a more comprehensive and precise risk profile for risk communication and stratification.

Identifying high-risk patients: Patients with high mFI and/or elevated SII may be at increased risk for postoperative complications and recurrence. These patients may benefit from a more thorough preoperative workup, including multidisciplinary team (MDT) consultation, to support individualized planning.

Guiding operative decisions: For patients identified as higher-risk, surgical candidacy and perioperative planning may warrant re-evaluation, and tailored strategies (e.g., minimally invasive approaches or staged procedures) could be considered within an MDT framework. These considerations should complement, rather than replace, tumor stage, resectability, and standard oncologic indications.

Informing prehabilitation strategies: Once frailty or significant inflammation is identified, targeted prehabilitation may be considered. Prehabilitation is a multimodal intervention designed to improve physiological and psychological status before surgery through exercise, nutritional optimization, and psychological support[27,28]. For malnourished frail patients, enhanced enteral or parenteral nutrition may be necessary[3]; for sarcopenic patients, progressive resistance training may be recommended[28]; for patients with chronic inflammation, optimization of chronic disease management and consideration of anti-inflammatory measures may be indicated. However, the extent to which mFI/SII-guided prehabilitation improves postoperative outcomes in this population remains to be confirmed in prospective trials.

Predicting long-term outcomes: Because mFI and SII are associated with both short-term complications and long-term RFS, clinicians may use these indices to support prognostic communication and to inform the intensity of follow-up planning, while adjuvant therapy decisions should remain aligned with established oncologic guidelines and clinicopathologic risk factors.

Personalized perioperative management

Risk stratification based on mFI and SII may facilitate personalized perioperative care.

Anesthetic and surgical strategies: For high-risk patients, anesthesiologists should carefully evaluate anesthetic risk and opt for techniques that minimize physiological perturbation[29]. Surgeons should strive for minimally invasive approaches, reduce operative time, and limit tissue trauma to preserve physiological reserve.

Enhanced postoperative monitoring and early intervention: High-risk patients require intensified postoperative surveillance, vigilant monitoring of vital signs, drain outputs, urine output, and early recognition of complications[30]. Prompt interventions, such as aggressive infection control should be considered when complications arise. Anti-inflammatory strategies, where applicable, should follow standard indications rather than biomarker status alone.

Nutritional support and rehabilitation: Postoperative nutritional support is critical, particularly for frail patients, to promote wound healing and recovery[31]. Early mobilization and rehabilitation reduce pulmonary complications, lower the risk of venous thromboembolism, and accelerate functional recovery.

Long-term follow-up and adjuvant therapy: Patients whose mFI and SII profiles suggest poorer RFS may warrant closer postoperative follow-up. Decisions regarding adjuvant therapy should be individualized according to established oncologic criteria, with mFI/SII serving as supportive, not determinative-information.

Promoting multidisciplinary collaboration

Implementing this risk stratification paradigm may benefit from close collaboration among MDT members. Surgeons, anesthesiologists, geriatricians, nutritionists, physiotherapists, and psychological counselors should jointly participate in assessment and management. Geriatricians can perform comprehensive geriatric assessments to identify frailty, malnutrition, and cognitive impairment; nutritionists can design individualized nutrition plans; physiotherapists can lead prehabilitation and postoperative rehabilitation. MDT care may support comprehensive, integrated, patient-centered management for elderly CRC patients.

CHALLENGES AND FUTURE DIRECTIONS

Although Qi et al’s research offers important insights, several challenges and avenues for future investigation remain[5].

Standardization and feasibility of indices

Although mFI and SII are effective predictors, their calculation and application require further standardization. While SII is straightforward, the specific components and scoring of mFI may vary across studies. Future work should evaluate the reproducibility and generalizability of these indices across populations and clinical settings. Additionally, integrating these measures seamlessly into routine workflows and ensuring their feasibility in resource-limited settings are practical considerations.

Dynamic assessment and intervention efficacy

Qi et al[5] primarily assessed preoperative mFI and SII, but frailty and inflammatory status are dynamic and may change with disease progression or therapeutic interventions. Future studies should investigate serial measurements of mFI and SII during treatment and determine whether dynamic changes better predict outcomes. Critically, randomized controlled trials are needed to test whether interventions guided by mFI and SII-such as targeted prehabilitation or anti-inflammatory strategies, actually improve clinical outcomes in elderly CRC patients. Accordingly, at present, mFI and SII should be viewed primarily as tools for risk stratification and prognostic assessment, rather than definitive triggers for specific perioperative interventions.

Integration with other biomarkers

Beyond mFI and SII, numerous other biomarkers may relate to outcomes in elderly CRC patients, such as CRP, serum albumin, lymphocyte count, and NLR, aggregate index of systemic inflammation, albumin-to-alkaline phosphatase ratio, pan-immune-inflammation value, inflammatory burden index, etc.[32-37]. Future research should explore how to combine these measures with mFI and SII to construct more comprehensive and powerful predictive models. With advances in genomics, proteomics, and metabolomics, additional biomarkers may emerge to enable even more precise individualized risk assessment.

Targeted interventions against inflammation and frailty

Given the central roles of frailty and inflammation in determining prognosis, another key research direction is developing targeted interventions addressing these mechanisms[38]. Can anti-inflammatory therapies mitigate systemic inflammation and improve perioperative outcomes? Are there pharmacologic or biologic strategies to reverse or attenuate sarcopenia and frailty? Investigating such interventions may yield strategies that fundamentally improve outcomes for elderly CRC patients.

Optimizing clinical pathways and generating evidence

Incorporating mFI and SII into clinical practice requires optimizing existing clinical pathways: Creating preoperative assessment algorithms, establishing perioperative management guidelines, and defining long-term surveillance strategies based on these indices. To promote adoption, high-quality evidence is necessary: Large multicenter studies and prospective randomized trials are essential to validate the effectiveness and safety of practice changes guided by mFI and SII.

CONCLUSION

Qi et al’s study marks an important milestone in risk assessment for elderly CRC patients[5]. By positioning the mFI and SII at the core of preoperative evaluation, the study advances a shift from chronological to biological perspectives on risk stratification. This paradigm may facilitate more precise identification of high-risk patients and support individualized perioperative planning, while highlighting the biological interplay between frailty and systemic inflammation. Nonetheless, evidence to date primarily supports their prognostic value, and the clinical benefit of interventions guided by mFI/SII requires prospective validation.

Looking ahead, we anticipate further studies to standardize these indices, explore their dynamic behavior, and integrate them with other biomarkers into robust predictive models. Most importantly, randomized clinical trials are needed to evaluate whether targeted interventions-including prehabilitation, individualized perioperative care, and therapies addressing inflammation and frailty, can improve quality of life and long-term survival for elderly CRC patients.

The ultimate goal is to deliver truly personalized care to every older patient with CRC: Irrespective of chronological age, each patient should receive tailored assessment, preparation, and treatment based on their unique physiological status, frailty level, and inflammatory profile. By adopting a biologically oriented risk stratification strategy rather than a strictly age-based one, we may improve perioperative risk communication and support more individualized care pathways. Such an approach should be implemented alongside standard oncologic decision-making, with future trials clarifying whether biomarker-guided strategies translate into measurable outcome gains.