Functional Assessment and Prehabilitation

The Physiologic Impact of Cancer and Surgery on Patient Function

As the volume and complexity of surgical procedures will increase in the next decades, the age and number of associated comorbid conditions of patients presenting for these procedures is also projected to rise. In this context, preventative strategies aimed at reducing postoperative complications by mitigating the stress response to cancer and surgery before it occurs is an area of increasing clinical activity and research.

The physical, metabolic, emotional, and systemic impacts of cancer on patient function while waiting for surgery are compounded by the effects of age, frailty, comorbidities, and cancer treatment. Frailty is a syndrome associated with decline across multiple organ systems with effects on cognitive, psychologic, and social well being, resulting in impaired homeostatic reserve and physical activity. The presence of cancer exacerbates the influence of disability and chronic disease on frailty. Over half of older patients with cancer have frailty or prefrailty, and this results in a progressive decrease in resiliency and adaptive capacity to stressors such as surgery and related neoadjuvant treatments such as chemotherapy and radiotherapy. This makes frail patients extremely vulnerable to postoperative complications.

Patients with cancer diagnoses awaiting surgery frequently lose lean body mass (LBM) due to age-related factors and immobility, while fat mass remains constant or increases. This combination of decreased LBM and increased body mass index (BMI), defined as sarcopenic obesity (SO), represents an extreme state of vulnerability to adverse postoperative outcomes. Cancer-related cachexia is also another multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) and leads to progressive functional impairment. Notwithstanding the fact that there remains considerable variation in definitions of these terms, methods of assessment, and cutoff values for these entities, underpinning many of these overlapping concepts is the common thread of reduction in functional capacity and activity.

In patients presenting for cancer surgery, the effects of frailty, multiple comorbidities, sedentary lifestyle, and neoadjuvant treatments have been described as “multiple hits” to the oxygen cascade and cardiovascular reserve capacity (CVRC). These “multiple hits” result in progressive reduction in patients’ functional capacity.

The impact of a cancer diagnosis requiring surgery has been shown to adversely affect all modalities of quality-of-life measures, especially affecting the domains of vitality and mental health. Among the common emotional responses to a cancer diagnosis, fear, anxiety, and worry appear to have the most relevance to patients’ abilities to cope with the diagnosis and make choices related to their treatments. These emotions can both facilitate decision-making and at the same time serve as barriers for making choices available to them, such as prehabilitation.

The Surgical Insult and the Importance of Preparing Patients for Stress

Similar to increased activity and intense exercise, the stress of surgery and the postoperative period are associated with an increase in oxygen consumption (V̇o ₂ ) especially in states of acute inflammation or sepsis. The inability to match oxygen delivery to increased oxygen demand is associated with anaerobic metabolism, and this is not sustainable, neither during exercise nor in the postoperative period. This inability to reduce oxygen debt at times of “stress” has been putatively proposed as the underlying mechanism for developing postoperative complications. ^, In a meta-analysis of more than 3632 patients with adult onset cancer, exercise was found to be safe and effective in increasing V̇o _2peak compared with no exercise.

Multiple clinical studies, including the recent Measurement of Exercise Tolerance before Surgery (METS) study and a study by Barberan-Garcia et al., have demonstrated the significance of oxygen carrying mechanisms in terms of prognosticating and optimizing patients for postoperative complications and long-term disease-free survival after major cancer surgery.

The Enhanced Recovery After Surgery (ERAS) program has identified some determinants of the surgical stress response, which lead to hyperglycemia and protein catabolism. With the understanding of the pathophysiology of the stress response and insulin resistance, ERAS elements, such as minimally invasive surgery, multimodal analgesia, oral carbohydrate drink, early mobilization, and early nutrition, have shown an impact on postoperative recovery.

More recent trials that have combined multimodal prehabilitation with ERAS programs appear to result in increased postoperative functional capacity and improved disease-free survival.

Changes brought about at various points in the oxygen cascade, such as optimization of cardiac output, improved ventilatory capacity, matching of lung ventilation to perfusion, increased oxygen carrying capacity, improved antiinflammatory effects, and increased end-organ capillary and mitochondrial density, may explain the possible impact of perioperative optimization.

Functional Assessment and Risk Stratification

Preoperative risk assessment is commonly based on the presence of medical comorbidities and on the invasiveness or clinical setting of the surgical procedure (elective vs. emergency). As a result, physicians commonly utilize general or organ-specific scoring systems that include a variety of medical conditions and/or surgical factors to stratify preoperative risk.

Despite extensive evidence demonstrating that poor preoperative functional capacity is associated with prolonged hospital stay, increased morbidity and mortality, decreased quality of life, and level of independence, ^, the importance of measuring preoperative functional capacity is frequently underestimated and inconsistently or inadequately measured. Recently, the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Surgical Risk Calculator incorporated the level of functional dependency and basic geriatric assessment measures to predict not only complications, but also functional decline, postoperative delirium, the use of a mobility aid, and the probability to be discharged to a nursing or rehabilitation facility ( https://riskcalculator.facs.org/RiskCalculator/ ).

Aging, comorbidities, physical fitness, and nutritional and psychologic status are the main pillars of functional capacity. Preoperative functional capacity of oncologic patients can be weakened by several factors: some related to their underlying diseases, such as malnutrition, cachexia, sarcopenia, frailty, depression, anxiety, and anemia; others related to the oncologic treatment, such as chemotherapy, radiotherapy, and/or surgery.

As preoperative functional capacity is complex in nature, its assessment cannot rely on a single preoperative test. Moreover, measuring functional capacity with multiple tools could be particularly useful when patients have physical limitations that prevent daily activities (e.g., musculoskeletal or neurologic disorders, obesity or pain) and therefore the use of certain tests. Today, several tests can be used in the preoperative period to estimate patients’ functional capacity ( Table 15.1 ). (a)The Cardiopulmonary Exercise Test (CPET) is considered the gold standard for measuring cardiorespiratory capacity. It is a noninvasive stress test that measures patient’s functional reserve, providing objective information on the integrated cardiopulmonary and musculoskeletal function. It allows for the determination of the oxygen consumption at the anaerobic threshold (V̇o _2AT ) and the peak oxygen consumption (V̇o _2peak ) through the analysis of breath-by-breath ventilation volumes, oxygen consumption, and carbon dioxide production. These variables inform the perioperative physician about the patient’s ability to withstand the increased metabolic demand induced by surgical stress. Several studies conducted in different surgical populations have demonstrated that poor functional capacity as measured by different CPET-derived variables, such as V̇o _2AT, V̇o _2peak , or ventilatory equivalent for CO ₂ at the AT (V̇e/ V̇co ₂ at AT), are associated with adverse outcomes. ^, In general, a V̇o _2AT <10–11 mL/kg/min and a V̇o _2peak <15 mL/kg/h may identify high-risk patients. V̇o _2AT and V̇o _2peak should always be expressed as a percentage of the age-predicted V̇o _2max , because V̇o ₂ physiologically declines with age. These variables not only inform about surgical risk, but also guide physicians to plan the appropriate intensity of perioperative care (e.g., advanced monitoring, intensive care admission vs. high-dependency unit vs. surgical wards), and develop tailored preoperative interventions aiming at improving functional capacity and thus attenuating surgical risk. ^, However, performing CPET is not always feasible, and it is resource-intensive and costly. Moreover, interpretation of its results requires appropriate training, as V̇o _2AT can be influenced by several factors and produce misleading results. These could consequently lead to an inappropriate clinical management.

It is common practice to measure preoperatively functional capacity by estimating metabolic equivalents (METs). This is also recommended by several international guidelines on preoperative risk assessment. ^, In fact, estimation of METs is a key element in deciding whether patients will require further preoperative evaluation and if patients are “fit” for surgery. Traditionally METs equivalent less than 4 (i.e., the ability of a patient to climb 1–2 flights of stairs in the absence of symptoms) has been associated with an increase in complications. However, recent evidence strongly discourages from continuing to subjectively assess preoperative functional capacity. In fact, the results of a recent international prospective cohort study, including 1401 patients (METS trial), have clearly demonstrated that preoperative subjective assessment of functional capacity (estimating METs by asking patients questions about common daily activities) is inadequate for predicting 30-day death or complications after major elective noncardiac surgery. Most importantly, the authors demonstrated that a subjective assessment of poor functional capacity (<4 METs) had a sensitivity of 19.2% (95% confidence interval [CI], 14.2–25.0) and a specificity of 94.7% (95% CI, 93.2–95.9) for identifying patients with peak oxygen consumption of <14 mL/kg/min (equivalent to <4 METs). These important findings demonstrate that preoperative physicians should correctly identify patients reporting poor fitness (positive likelihood ratio, 3.8). However, among those physicians rating adequate exercise tolerance, poor cardiopulmonary fitness is missed 84% of the time (negative likelihood ratio, 0.85). This implies that several high-risk patients with poor functional capacity, and that could be potentially optimized, are improperly “cleared” for surgery when objective and more sensitive measures of physical fitness are not utilized in the preoperative period. These findings have also been confirmed by the results of the recent National Health and Nutrition Examination Survey conducted in 522 nonsurgical patients. (b)Dynamic tests, such as the 6- and 2-min walking tests, shuttle walking test, timed up and go (TUG), and gait speed, have also been used to measure preoperative functional capacity and predict surgical risk and postoperative recovery. The 6- and 2-min walking tests evaluate the ability to maintain a moderate level of physical activity by measuring the distance covered over 2 or 6 min. These tests are easy to apply and can be used as screening tools to identify high-risk patients with reduced functional capacity who deserve a more thorough and accurate evaluation (e.g., CPET). Moreover, in high-risk patients, 6-minute walk test (6MWT) distance weakly correlates with both 12-month disability-free survival (Spearman’s correlation coefficient [ρ] = –0.23; P < 0.0005) and 30-day 15-item quality of recovery (ρ = 0.14; P < 0.001). Its sensitivity and specificity improve when patients walk short distances (<370 m). (c)The Duke Activity Status Index (DASI) is a self-administered questionnaire that was originally developed and validated as a measure of functional capacity and to predict V̇o _2peak in nonsurgical cardiovascular patients. In fact, this score moderately correlates with V̇o _2peak (ρ = 0.58, P < 0.001). In contrast to the 6MWT or the CPET, where the assessment of functional capacity depends on the patient’s performance during the test, the DASI includes measures of physical and emotional fitness covering a period of time, thus better reflecting overall patient functional capacity. Not surprisingly, the DASI has been recently shown to predict 30-day death or myocardial infarction after major elective noncardiac surgery (adjusted odds ratio [AOR], 0.91; 95% CI, 0.83–0.99; P = 0.03), while V̇o _2peak or N-terminal pro-B-type natriuretic peptide (NT-pro BNP) have not. In the same study, the DASI also predicted 30-day death or myocardial injury (AOR, 0.96; 95% CI, 0.92–0.99; P = 0.05). Interestingly, in a secondary analysis of the METS trial, the DASI predicts 12-month disability-free survival (AOR, 1.06; P < 0.0005), better than the 6MWT (area under the curve [AUC], 0.63; 95% CI 0.57–0.70) and the V̇o _2peak (AUC, 0.60; 95% CI, 0.53–0.67), further confirming the clinical utility of this multidimensional assessment tool.

In an observational study of 50 elderly patients undergoing major abdominal surgery and in whom functional capacity was measured with different tests, a DASI score ≥46 has been proposed as a threshold to identify high-risk patients (V̇o _2AT ≤11 mL/kg/min and V̇o _2peak ≤15 mL/kg/min; positive predictive value, 1.00). However, it underestimated functional capacity in almost two-thirds of low-risk patients (negative predictive value, 0.40). These results suggest that a DASI score <46 should not be used as a single test to identify high-risk patients. Moreover, larger validation studies are needed to confirm this threshold and its association with clinical outcomes. (d)Most recently, plasma brain natriuretic peptides such as the brain natriuretic peptide (BNP) or the NT-pro BNP have been proposed as biomarkers to estimate cardiovascular risk and functional capacity. BNPs are mainly produced by cardiomyocytes in response to ventricular and atrial stretching (mechanical strain), but other causes such as inflammation and hypoxia can trigger its release. High plasma BNP and NT-proBNP concentrations are frequently measured in patients with a variety of chronic and acute cardiac conditions, such as ventricular hypertrophy, diastolic dysfunction, and congestive heart failure. In this clinical context, the prognostic value of plasma BNPs has been well established. Similarly, the prognostic value of plasma BNP/NT-pro BNP has also been demonstrated in surgical patients undergoing major noncardiac surgery. Patients with high preoperative BNP/NT-pro BNP concentrations were more likely to develop postoperative 30-day cardiac complications, including death, cardiovascular death, and myocardial infarction (odds ratio [OR], 44.2; 95% CI, 7.6–257). Recently, the ability of the NT-pro BNP to estimate functional capacity has been evaluated. The results of the METS trial demonstrate that NT-pro BNP negatively correlates with V̇o _2peak (Spearman ρ = –0.21, P < 0.0001), and positively with the DASI (Spearman ρ = 0.43, P < 0.0001). However, it predicts 30-day death or myocardial injury (AOR, 1.78; 95% CI, 1.21–2.62; P = 0.003), 1-year death (AOR, 2.91; 95% CI, 1.54–5.49; P = 0.001), but not disability-free survival (AUC, 0.56; 95% CI, 0.49–0.63, P = 0.08) or in hospital moderate or severe complications (AUC, 1.10; 95% CI, 0.77–1.57; P = 0.61). ^, Estimating preoperative functional capacity by measuring preoperative BNPs may be useful in patients with physical impairments or in the preoperative setting with limited personnel or resources. However, further research is needed to understand the causes of high plasma BNP levels and to validate these biomarkers as accurate measures of functional capacity.