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.

Table 15.1

Utility of Preoperative Cardiopulmonary Exercise Testing (CPET)

Grade of the Recommendation

To estimate the likelihood of perioperative morbidity and mortality and contribute to preoperative risk assessment
To inform the processes of multidisciplinary shared decision-making and consent
To guide clinical decisions about the most appropriate level of perioperative care (ward vs. critical care)
To direct preoperative referrals/interventions to optimize comorbidities
To identify previously unsuspected pathology
To evaluate the effects of neoadjuvant cancer therapies including chemotherapy and radiotherapy.
To guide prehabilitation and rehabilitation training programs
To guide intraoperative anesthetic practice

B
C
C
C
B
B
B
D

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.

Prehabilitation

Prehabilitation can be defined as the process that initiates before surgery and enables patients to enhance their functional capacity in anticipation of surgical stressors. The term, as proposed by Topp, is opposed to rehabilitation where the intervention occurs after surgery.

Another definition of prehabilitation for oncology was proposed by Silver and is more comprehensive: “A process on the cancer continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment and includes physical and psychological assessments that establish a baseline functional level, identify impairments, and provide interventions that promote physical and psychological health to reduce the incidence and/or severity of future impairments.”

The explanation of the term prehabilitation is based on understanding that by applying an interventional program aiming at improving functional ability before the stress of surgery, patients would retain a higher level of functional reserve over their entire surgical admission. It would then mean that postoperative recovery would occur more rapidly compared to patients who remain inactive throughout the whole surgical admission ( Fig. 15.1 ).

While the prehabilitation cancer literature in the first instance focused on exercise as a single modality intervention, recent studies have highlighted the importance of other modalities such as nutrition, either together with exercise or alone. The addition of psychologic strategies to the other two elements, as part of the prehabilitation program, in cancer patients with depression demonstrates how important the trimodal approach is in the enhancement of functional capacity. This model represents a much more holistic approach and is based on the understanding that physical fitness, optimal nutrition, and emotional well being are closely interrelated and complement each other.

Furthermore, the more general scope of prehabilitation recognizes that nonexercise interventions, as mentioned above, may also be beneficial to a specific population, as well as prescribing exercise as a single modality. This supports the concept that prehabilitation is not a “one size fits all” program but rather involves specific, individualized assessments and structured interventions delivered by a team of experts.

Successful surgery is dependent upon many factors—anesthesia, surgery, surgical care, and most importantly on how well the patient is able to return to a physically and psychologically healthy state. While fast track and ERAS protocols have been shown to shorten the length of hospitalization, it is important to consider how well, physically, nutritionally, and emotionally, patients need to be before surgery in order to facilitate their recovery process once discharged from the hospital. In view of this, there is strong published evidence that low cardiorespiratory fitness not only limits access to surgery and other therapies, but also that when patients are operated on, the risk of postoperative complications, and mortality is high. The question is whether surgeons wish to operate on deconditioned frail elderly patients or run the risk of the cancer spreading due to delays to surgery. A commonly accepted position would be to accept a delay of 4 to 6 weeks of prehabilitation in patients presenting for high-risk surgical procedures.

Recent studies have shown that prolonging the time interval between diagnosis and surgery does not impact the immediate- and long-term outcome in patients scheduled for elective colorectal cancer resection. This would imply that optimization of patients’ health status can be justified in those who are at high risk of postoperative complications. ^,

Prehabilitation not only prepares the cancer patient in anticipation of the surgery, but also plays an important role in continuing the best comprehensive care and subsequent cancer treatment, as chemotherapy, radiotherapy, and hormonal treatment are all known to have a negative impact on functional capacity. This can also be said for those patients who undergo neoadjuvant therapy followed by surgery. In fact, poor physical and nutritional statuses have been identified as important reasons for low adherence and responsiveness to neoadjuvant therapy. In addition, delays in the commencement of adjuvant treatment due to poor physical status are associated with higher mortality rates.

In light of these important concerns, there is a growing interest in prehabilitation as a part of a cancer care continuum for the prevention and/or attenuation of treatment-driven disorders, improvement in access, and adherence to treatment.

While in principle all patients anticipating cancer surgery can be enrolled in a prehabilitation program, there is a need to assess individual patients and determine whether some conditions can be modified during the time interval between diagnosis and surgery. This is particularly true for different types of cancer, the age of the patient, comorbidities, and the site where the prehabilitation can be conducted. While some comorbidities and patient factors cannot be modified, others, such as smoking cessation, sedentary activity, poor nutrition, and high anxiety, can be amenable to modification. This requires a concerted action by an interdisciplinary group working on a common platform. Patients who are frail with low fitness and low functional reserve can improve their functional capacity over a minimum period of 4 weeks before colorectal cancer surgery when multimodal prehabilitation is administered. In the case of malnutrition, which is very common in cancer patients, a minimum of 7–10 days of either enteral or parenteral nutrition is recommended.

The initial assessment of patient fitness from the physical, nutritional, and mental point of view would determine the necessity to plan an intervention that includes various elements with the intention to create a synergy between them. This of course needs to consider patient comorbidities and access to care. All these elements represent the potential risk factors (sedentary activity, malnutrition, anxiety, depression) that feature in the pathogenesis of cancer. Therefore it becomes necessary to determine how to modulate these elements to counteract the negative impact of these factors on outcome. The concept of the multimodal, synergistic effect of these elements needs to be integrated with other interventions, such as the optimization of medical morbidities, smoking and alcohol cessation, and modification of surgical care within the (ERAS) pathway programs.

Exercise and Physical Activity for the Surgical Cancer Patient

It is becoming increasing clear that a paradigm shift must occur, moving from the traditional belief that a patient must rest in preparation for surgery to a more proactive approach with the goal of optimizing patient functional status in the preoperative time frame. Physical inactivity and bed rest are associated with insulin and protein resistance, which together contribute to increased systemic inflammation and loss of muscle mass. This may, in addition, further exacerbate preexisting age-related comorbidities, such as low cardiovascular fitness, sarcopenia, and insulin resistance/diabetes. All of these factors not only hinder the cancer patient’s ability to cope with acute treatment, such as surgery, chemotherapy, or radiation therapy, but can also impact the patient’s recovery and potentially, postpone subsequent intervention.

A conventional approach to improving patient physical status focuses on rehabilitating the patient after treatment. Although there are clear benefits from posttreatment intervention, it may be more challenging to initiate and adhere to major behavioral changes such as commencing an exercise program when the patient is both mentally and physically stressed and in the early stages of recovery. This may be especially challenging when the individual is already facing a diminished functional status resulting from sedentarism in the pretreatment phase, as depicted in Fig. 15.1 . Recent advances in the area of prehabilitation support the notion that the pretreatment phase is an important opportunity to both physically and mentally optimize the patient in order to mitigate the decline in functional status and enhance the recovery process.

Physical activity has been defined as any bodily movement produced by skeletal muscles that results in energy expenditure. Exercise, however, encompasses a subset of physical activity that is planned, structured, and repetitive and aims to improve or maintain physical fitness. Physical fitness describes and quantifies a set of attributes that are either health- or skill-related and can be measured by specific tests or assessments. These tests or assessments will not only provide insight into the patient’s baseline but also how each individual responds to the exercise stimulus. In order to optimize patient functional status and encourage program adherence, a comprehensive prescription may include both a physical activity and exercise component. The exercise component, in particular, should also be accompanied by regular assessments in order to ensure that the patient is training effectively. This combination will not only serve as a backbone for presurgical intervention but can also provide important groundwork for the postoperative period and beyond.

A structured exercise program includes either some or all of the following training elements, depending on the specific needs and abilities of each patient: cardiovascular, resistance, flexibility, neuromotor (balance), and respiratory ( Table 15.2 ). Each exercise session should also include a warm up and cool down, which allows for the patient to physiologically transition in and out of exercise.

Table 15.2

Goals, Guidelines, Specifics, and Strategies for Exercise, Physical Activity, and Nutrition in the Presurgical Period

Goal	Guideline	Specifics	Strategies
Improve cardiovascular fitness	Accumulate 150 min of moderate to vigorous activity per week.	150 min can be divided into multiple sessions per week (i.e., 30 min per session, 5 times per week). Intensity should be between 5–8/10 on Borg scale.	Swimming, jogging, brisk walk, aerobics class, or other continuous activity that the patient can perform safely and enjoy.
Improve skeletal muscle fitness	Exercise all major muscle groups, for at least one set of 8 to 12 repetitions. Patient should find last repetition challenging.	Strength exercises should happen every second day to allow for adequate recovery. If patient finds it easy to complete 12 repetitions, resistance should be increased. Ensure that motion is controlled and both concentric and eccentric phases are equal in velocity.	Resistance bands, hand weights, barbells, gym equipment. Pay attention to strain at joints.
Increase amount of weekly physical activity	Accumulate a minimum of 30 min of physical activity per day.	Light intensity activity, between 3 and 4/10 on Borg scale, can be broken up over days.	Patient should perform physical activities that may include gardening, walking, bicycle rides, dancing, housekeeping
Improve balance	Include balance exercises if necessary.	Perform exercises that involve balance on one leg or agility tests. Activities will be dependent on abilities of patient.	Patient can perform yoga, tai chi, and other exercises specific to needs.
Improve flexibility	Include flexibility exercises.	Hold stretches for at least 20 s to point of “tightness” but not to pain. Activities will be dependent on abilities of patient.	Patient can perform lunges, attempt to touch toes (standing or seated), attempt to “scratch back.”
Reduce sitting/sedentary time	Provide strategies for breaking up sitting time.	Patient should not be immobile for more than 30 min without moving or standing.	Every 30 min, patient should use strategies to move or stand.
Goal		Strategy
Establish whether a nutrition-based intervention is required in the presurgical period		Perform a detailed analysis of patient dietary habits, along with relevant hospital tests at baseline.
Intervene if patient is malnourished or at risk for malnourishment		Provide nutritional counseling or supplementation and follow up to ensure patient improvement.
Time protein ingestion throughout day		Plan daily diet with patient to include protein (approximately 25–35 g) at each meal.
Time protein ingestion postexercise to take advantage of “anabolic window”		Ingest an easily digestible protein (i.e., whey protein) within 90 min postexercise.