Sarcopenia and Frailty in Lung Cancer

Introduction

In 2020, lung cancer was the second most diagnosed cancer and the leading cause of cancer death worldwide causing an estimated 1.8 million deaths. This disease is broadly divided into two histologic subtypes: small cell (SCLC) and nonsmall cell lung cancer (NSCLCs). The clinical presentation of lung cancer is widely varied but often correlates with anatomic location of the tumor within the bronchial tree. Radiation, chemotherapy, surgery, and targeted therapy can all be employed as treatment options dependent upon many patient and tumor factors. Unfortunately, lung cancer is often diagnosed in advanced stages leading to a high morbidity and mortality in this disease. Clinical outcomes in lung cancer are known to be associated with specific tumor-related factors such as histologic type, size of the tumor, nodal involvement, and evidence of metastases. However, other host factors, such as sarcopenia and frailty status, have also demonstrated significant prognostication of morbidity and mortality among individuals with this malignancy. Sarcopenia is defined as the triad of loss of muscle mass or quality, reduced muscle strength, and impaired physical performance. Frailty is described as a multidimensional syndrome characterized by vulnerability to minor stressors leading to an increased risk of adverse outcomes. Both conditions ultimately predispose to functional decline, and thus are important to recognize in the clinical setting. Unlike intrinsic properties of an individual's lung cancer, sarcopenia and frailty are potentially modifiable. This makes both sarcopenia and frailty attractive targets for interventions that may lead to improved outcomes in this patient population. Physiatrists, particularly cancer rehabilitation specialists, are uniquely positioned to play a pivotal role in both the diagnosis and treatment of sarcopenia and frailty in patients with lung cancer.

Definition of Sarcopenia

Sarcopenia is defined by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) as a “progressive and generalized skeletal muscle disorder that is associated with increased likelihood of adverse outcomes including falls, fractures, physical disability, and mortality.” According to EWGSOP2, the diagnosis of sarcopenia is probable when low muscle strength is detected, and it is confirmed when low skeletal muscle mass or skeletal muscle quality is demonstrated on imaging. Often, the proposed cut-off value for sarcopenia is appendicular skeletal muscle mass index (SMI) greater than two standard deviations below the sex-specific mean in healthy adults. If impairments of both muscle strength and quantity occur in conjunction with impaired physical performance, sarcopenia is qualified as severe. The EWGSOP2 definition of sarcopenia is just one of many definitions for this condition. Research in sarcopenia is evolving and thus many definitions have been proposed; most definitions involve some degree of loss of muscle mass, quality, strength, and performance. The latter two elements are important to remember. Without the findings of impaired muscle strength and function, an individual would be more appropriately diagnosed with malnutrition. Sarcopenia is not simply decreased muscle mass; it encompasses overall muscle function, thus more closely pertaining to the global function of the individual.

Primary sarcopenia is a natural component of the aging process. Advanced age inevitably leads to decreased muscle mass and strength. This process often begins in the fourth or fifth decade of life and continues until death. Secondary sarcopenia arises in the setting of chronic inflammatory conditions such as cancer, physical inactivity, and inadequate macronutrient intake. Like sarcopenia, cancer is often a disease of aging. Thus, accounting for both primary and secondary sarcopenia, it is understandable why sarcopenia is highly prevalent in the cancer population. In fact, sarcopenia is now the hallmark component of the formal definition of cancer cachexia, a condition which has long been understood to negatively affect those afflicted with various malignancies. Muscle mass decrements, however, predate most clinical signs of cancer cachexia. In other words, sarcopenia is present prior to the weight loss and anorexia seen in cachexia. Therefore, it is essential to evaluate for the presence of sarcopenia in cancer patients prior to progression to clinical cachexia. It is additionally important to note that sarcopenia is not only present in underweight or thin individuals. Body mass index (BMI) has previously been used as a marker for nutritional status and function in cancer patients, but as the U.S. population becomes more obese, this measure has not been shown to accurately indicate muscle depletion. Loss of muscle mass is often present even when a patient's BMI is normal or elevated. The term sarcopenic obesity is used to describe this phenomenon of decreased muscle mass with concomitant elevated fat mass. Thus, there is no one phenotype for the sarcopenic patient; sarcopenia can be present in a cachectic 80-year-old lung cancer patient but can also be diagnosed in an overweight 60-year-old lung cancer patient.

Definition of Frailty

In 2004, the American Geriatric Society defined frailty as “an excess vulnerability to stressors, with a reduced ability to maintain or regain homeostasis after a destabilizing event.” Continued insults in frailty lead to an eventual functional decline. It is known that decreased functional reserves increase the risk of hospitalization, falls, and disability in the geriatric population. In the cancer population, the added stressors of the disease itself and treatments such as surgery, chemotherapy, and radiation may ultimately prove too taxing for the frail patient. Thus, cancer can be seen as a “frailty stress test.”

There are two main approaches of assessing frailty as a syndrome: the phenotypic definition and the accumulation of deficits definition. In the phenotypic definition, frailty is understood to be a physical condition. It is characterized by weight loss, exhaustion, weakness, slowness, and low physical activity. Three out of these five components must be present to deem an individual as “frail” using the phenotypic definition. Conversely, an alternate approach to assessment of frailty is characterized by an accumulation of deficits. Using this approach, each additional medical symptom, functional impairment, psychosocial issue, and laboratory abnormality present in an individual increases their likelihood of frailty. Most indices use between 30 and 70 variables to determine frailty. To be included, a variable must be “biologically sensible, accumulate with age, and does not saturate too early,” meaning it is not too highly prevalent at a young age. Once a sum of deficits is determined, an individual can be classified as fit, prefrail, or frail with different cut-off values depending on which index of deficits is used.

With sarcopenia and frailty defined, it is evident that these two concepts are closely intertwined. However, it is important to distinguish these two discrete entities. Sarcopenia is a disease state of muscle, while frailty is a syndrome in which multiple physical and psychosocial domains decline over one's lifetime. Sarcopenia can contribute to frailty, but frailty has much broader implications.

Prevalence of Sarcopenia and Frailty

Due to the various definitions, populations, and cut-off values used when studying sarcopenia, there are broad ranges of prevalence reported in the literature. Sarcopenia is known to increase with age and with increased medical complexity. About 15% of healthy adults over age 45 and about 60% of adults over age 85 were found to be sarcopenic in one study. In another meta-analysis, the prevalence of EWGSOP-defined sarcopenia in community-dwelling adults was found to be in the range of 1%–29%. In that same meta-analysis, prevalence of sarcopenia in those living in long-term care centers ranged from 14% to 33%. The prevalence of sarcopenia in individuals with nonsmall cell lung cancer (NSCLC) has been reported to be up to 50%, indicating that one of every two patients with NSCLC is sarcopenic.

As with sarcopenia, prevalence of frailty is contingent upon the definition employed and the index used for measurement. Drastically different prevalence of frailty within a population can be seen using various frailty assessment tools due to differences in items measured. One study that used a large sample from the National Health and Aging Trends Study noted that 15% of an elderly, community-dwelling population were frail and 45% were prefrail. Frailty is more prevalent in women, racial and ethnic minorities, the elderly, and in low-income earners. In the cancer population, rates of frailty are even higher. One systematic review of 2916 elderly cancer patients found that the median prevalence for frailty and prefrailty were 42% and 43%, respectively. Within the lung cancer population, frailty prevalence rates range from 13% to 68%. Although the overall prevalence rates of sarcopenia and frailty are variable, these conditions significantly affect patients with lung cancer and should therefore be addressed routinely as part of their medical care.

Pathophysiology of Sarcopenia in Lung Cancer

It is important to understand the pathophysiology of sarcopenia itself, both as a primary mechanism and secondarily to cancer. Almost all loss of skeletal muscle mass in sarcopenia is of Type II (fast twitch) muscle fibers, as opposed to Type I (slow twitch) fibers. There are a few underlying mechanisms that are thought to contribute to this loss of muscle mass. First, multiple components of the neurologic system can be affected over time leading to an effective neuropathic process of muscle loss. Additionally, aging is associated with changes in hormone production and sensitivity to those hormones; decreased testosterone, increase cortisol, decreased vitamin D, and insulin resistance can all contribute to sarcopenia. These intrinsic changes along with other factors associated with aging, including immobility and poor nutrition lead to higher rates of sarcopenia in the elderly population. When thinking about cancer, the inflammatory nature of malignancy is what contribute to loss of muscle mass. Increased tumor necrosis factor-α, interleukin-6, interleukin-1, and CRP can lead to activation of cell-signaling pathways which lead to tissue degeneration. Even a chronic low-grade inflammatory state related to aging can be implicated in sarcopenia, so it follows that the elevated inflammatory response and metabolic changes in cancer also lead to this condition.