Clinical implications of low skeletal muscle mass in early stage breast and colorectal cancer

Abstract

Although obesity has now been widely accepted to be an important risk factor for cancer survival, the associations between body mass index and cancer mortality have not been consistently linear. Although morbid obesity has clearly been associated with worse survival, some studies have suggested a U-shaped association with no adverse association with overweight or lower levels of obesity. This “obesity paradox” may be due to the fact that body mass index likely incompletely captures key measures of body composition, including distribution of skeletal muscle and adipose tissue. Fat and lean body mass can be measured using clinically acquired CT scans. Many of the earlier studies focused on patients with metastatic cancer. However, skeletal muscle loss in the metastatic setting may reflect end stage disease processes. Therefore, this article focuses on the clinical implication of low skeletal muscle mass in early stage non-metastatic breast and colorectal cancer where measures of body composition have been shown to be strong predictors of disease-free survival and overall survival and also chemotherapy toxicity and operative risk.

Introduction

Although obesity has now been widely accepted to be an important risk factor for cancer survival ¹, the associations between body mass index and cancer mortality have not been consistently linear. Although morbid obesity (>35 kg/m2) has clearly been associated with worse survival, some studies have suggested a U-shaped association with no adverse association with normal/overweight, but worse outcomes with both underweight and higher levels of obesity. This “obesity paradox” may be due to the fact that body mass index likely incompletely captures key measures of body composition, including distribution of skeletal muscle and adipose tissue.² Fat and lean body mass can be measured in a variety of ways, including bioelectrical impedance electrical analysis, dual energy x-ray absorptiometry, magnetic resonance imaging, and computed tomography (CT) scans. With the exception of CT scans, most of the other types of scans are not routinely done on patients in the clinical setting. On the other hand, clinically acquired CT scans can be used to estimate both the muscle and adipose tissue compartments with high accuracy and are often done for staging or planning purposes at diagnosis and surveillance for a variety of early stage cancers, facilitating the incorporation of assessment of body composition into routine clinical care.³ Skeletal muscle mass can be precisely estimated from single-slice axial CT images at the third lumbar vertebra (L3). It should be noted that the cutpoints used to define sarcopenia (or low muscle mass) have varied considerably across studies, making cross-study comparisons difficult at times.³ Many of the earlier studies focused on patients with metastatic cancer where serial CT scans are readily available. However, skeletal muscle loss in the metastatic setting may reflect end stage disease processes that may not be generalizable to the non-metastatic setting and may not be easily reversible. Therefore, this article will focus on the clinical implication of low skeletal muscle mass in early stage non-metastatic breast and colorectal cancer where there may still be actionable findings and potential insights into mechanisms.

Potential mechanisms relating body composition and survival

While the precise mechanisms linking skeletal muscle to survival after a cancer diagnosis are not established, it is likely that skeletal muscle operates through physiologic and metabolic (e.g., inflammation) as well as behavioral (e.g., reduced physical activity due to de-conditioning and fatigue) pathways. Skeletal muscle has local autocrine and paracrine, and endocrine effects, but also secretes cytokines and other myokines (including interleukin (IL)-6, IL-8, IL-15, and leukemia inhibitory factor) leading to systemic effects.⁵ Therefore, higher levels of muscle may decrease the impact of obesity-induced inflammation,⁶ whereas lower levels of muscle could lead to local and systemic inflammation.⁷ Several studies suggest that systemic inflammation may lead to ongoing muscle loss in cancer patients and in part drive the associations with cancer survival.^8,9 In vitro studies also highlight the key role of inflammation. For example, exercise-induced myokines released from skeletal muscle, such as interleukin-6, suppress tumor growth.¹⁰ Loss of muscle may also disrupt oxidative pathways, encouraging tumor growth.¹¹ Muscle is also an important target of insulin-mediated glucose uptake and low muscle mass may be associated with insulin resistance.^12,13 Finally, low skeletal muscle may influence survival after a cancer diagnosis by its impact on other crucial cancer outcomes such as surgical complications and treatment-related toxicity leading to chemotherapy dose modifications or interruptions, which will be discussed in the following sections.

Colorectal cancer

Colorectal cancer is the second leading cause of cancer death both in the United Kingdom¹⁴ and in the United States.¹⁵ The search for modifiable risk factors to improve rates of recurrence and survival is therefore a public health priority. Overwhelmingly, the focus in early-stage colorectal cancer has been on excess adiposity with less attention to another major component of body composition: skeletal muscle mass. However, accumulating evidence suggests that low skeletal muscle mass at colorectal cancer diagnosis, often referred to as sarcopenia or myopenia, is highly prevalent and associated with cancer recurrence, survival, surgical complications and treatment-related toxicities. Studies using this technique included heterogeneous patient populations and variable cut-points to define “low” skeletal muscle mass, leading to a wide range of prevalence estimates (from 17%¹⁶ to 60%¹⁷) for sarcopenia.

Association with cancer recurrence and survival

Multiple studies evaluate the association of low skeletal muscle mass at colorectal cancer diagnosis with overall and recurrence-free survival.^{2,5,18, 19, 20} Fewer have examined colorectal cancer-specific survival in non-metastatic patients.^.2 One meta-analysis combined the results of three small studies, two of which were in metastatic colorectal cancer patients, and reported that low skeletal muscle at colorectal cancer diagnosis was associated with a more than two-fold risk of overall mortality (hazard ratio (HR)=2.25; 95% confidence interval (CI)=1.63–3.09).¹⁸ The largest non-metastatic cohort study published to date included 3,262 stage I-III colorectal patients diagnosed 2006–2011 and reported that patient with sarcopenia at diagnosis were at increased risk of both overall mortality (HR=1.27; 95% CI=1.09–1.48) and colorectal cancer-specific mortality (HR=1.46; 95% CI=1.19–1.79). This study utilized optimal stratification to determine BMI and gender specific cutpoints for sarcopenia (normal/overweight men <52.3 and women <38.6 cm²/m² and obese men <54.3 and women < 46.6 cm²/m²).² While heterogeneity in study design and patient population complicates the interpretation of this body of evidence and precludes a comprehensive meta-analysis, most studies report a statistically significant increased mortality for patients with low skeletal muscle mass. ^{2,5,18, 19, 20} To our knowledge, no study reports a protective association of low skeletal muscle mass.

Association with complications after colorectal cancer surgery

Several authors have reviewed the research on the associations between body composition and adverse cancer outcomes besides survival in colorectal cancer. ^19–22 In colorectal cancer specifically, multiple studies report higher risk of complications,^19–23 short-term mortality after surgery^19–22, and the need for postoperative rehabilitation.²³ The largest of these studies was by Malietzas et al who reviewed 805 patients (90% Stage I–III) undergoing elective colorectal cancer surgery resection and found that myopenic obesity was associated with a higher 30 day rate of major complications (22% vs 13%, p=0.019) and mortality (p>0.001).¹⁹ Lieffers et al also noted that sarcopenia was an independent predictor of higher rates of infection (Odds ratio (OR) = 4.6; 95% CI=1.5–13.9) and need for inpatient rehabilitation (OR= 3.1, 95% CI=1.04–9.4) among 234 colorectal cancer patients undergoing resection.²³ Similarly, studies have also reported longer hospital stays for patients with low skeletal muscle.^16,19,23 It should be noted that all of these analyses controlled for BMI and that body composition measures generally outperformed BMI in predicting risk of complications. In sum, the data from the colorectal cancer literature strongly suggest that assessments of body composition and skeletal muscle from CT scans could significantly impact preoperative risk assessment and improve decision-making around selection of candidates for surgery and post-operative treatment.^23,24

Associations with Treatment-Related Toxicities

Another important pathway through which low muscle could influence colorectal cancer survival is by reducing the efficacy of life-saving cancer therapies. Low muscle has been associated with treatment toxicities, dose reductions, and early discontinuation of chemotherapy - all of which potentially compromise the effectiveness of adjuvant therapies which are being administered with curative intent.²⁴ Most chemotherapies are dosed based on body surface area (BSA in meters squared, m²), for which the recommended milligrams per m² are derived from clinical trials assessing dose-limiting toxicities along with efficacy. Yet, many patients still experience severe toxicity and are subsequently dose-reduced, or treatment may be delayed or discontinued early. Multiple studies have shown that non-metastatic colorectal cancer patients with lower skeletal muscle consistently experience higher rates of grade 3/4 toxicity, such as neutropenia, diarrhea, neuropathy, and hand-foot syndrome.^25–29 Furthermore, another study found that among 533 non-metastatic colon cancer patients receiving FOLFOX chemotherapy, those in the lowest tertile of muscle mass were more likely to be dose-reduced (OR=2.28; 95% CI=1.19–4.36), dose-delayed (OR= 2.24; 95% CI=1.37–3.66), and to discontinue chemotherapy prematurely (OR= 2.34; 95% CI=1.04–5.24), than those in the highest tertile.³⁰

A possible explanation is that lower muscle may result in a smaller tissue volume for distribution of certain cancer therapies, with potentially lower capacity for metabolism and clearance of drugs, thereby leading to greater toxicity. Additionally, BSA dosing does not account for variation in muscularity, which has been hypothesized to influence the pharmacokinetics of chemotherapy.³¹ To our knowledge, only one study to date has examined the pharmacokinetics of 5-fluorouracil (5-FU) in patients receiving FOLFOX for colorectal cancer chemotherapy; the authors found no significant differences in first cycle 5-FU area-under-the-concentration-time-curve, though patients with a higher dose per kilogram lean body mass experienced greater toxciity.³² Ongoing trials (Clinical trials.gov NCT03291951) are testing the effectiveness of resistance training to increase muscularity and thereby decrease dose-limiting toxicity and increase chemotherapy completion rates among colon cancer patients.

Breast Cancer

Breast cancer is the most common cancer among women both in the United Kingdom¹⁴ and United States.¹⁵ Obesity is a well-established risk factor for breast cancer incidence and survival, but as described previously, although studies have clearly shown worse mortality with obesity, the association between breast cancer survival and overweight (BMI 25–30) have been less consistent, with some studies showing no adverse effect.^33–35 Body mass index only incompletely captures the more relevant physiologic measures of skeletal muscle and adipose tissue.

Association with cancer recurrence and survival

We conducted the largest study of the association of measures of body composition with breast cancer survival in the non-metastatic setting published to date. The study population included 3283 breast cancer survivors diagnosed with Stage II–III breast cancer from 2000–2012. Even in this non-metastatic community-based population, 34% of subjects were sarcopenic (defined as SMI <40 cm²/m²). Patients with sarcopenia showed higher overall mortality (HR=1.46; 95% CI= 1.23–1.74), compared to those without. In addition, patients in the highest tertile of total adipose tissue (TAT) also showed higher overall mortality (HR=1.35; 95% CI =1.08, 1.69), compared to those in the lowest tertile. The highest mortality was seen in the sarcopenic obese, those with both sarcopenia and high TAT (HR= 2.08; 95% CI= 1.44–3.01). BMI alone had a much weaker association with mortality and incorrectly classified some women at risk for adverse outcomes due to body composition.³⁶ Three other studies also evaluated the associations between body composition and survival among non-metastatic breast cancer patients. Before our study, the previous largest study to date included 471 non-metastatic breast cancer patients (stage l–lllA) and showed similar results with worse overall survival with sarcopenia measured by DEXA (HR =2.86; 95% CI= 1.67–4.89). However, all muscle measurements were taken after chemotherapy treatment.³⁷ Del Fabbro et al (2012) analyzed data from 129 non-metastatic breast cancer patients treated with neoadjuvant chemotherapy at MD Anderson Cancer Centre, Texas, USA.³⁸ Sarcopenia was defined as skeletal muscle index ≤ 38.5 cm²/m² measured by CT. There was a trend towards an association between sarcopenia and chance of pathologic complete response (OR=4.97; 95% CI=0.99–16.87) in the overall population. When limited to patients with a normal BMI (defined as <25 kg/m2), the odds for a response were higher among those with sarcopenia (OR=6.86; 95% CI=1.30–36.04). Although sarcopenia was not associated with overall survival time, patients with sarcopenic obesity had shorter progression-free survival time.³⁸ The smallest study (n=119) found similar results with sarcopenia (defined as skeletal muscle index < 41 cm2/m2 measured on CT) significantly associated with worse disease free (p=0.02) and overall (p=0.05) survival, whereas there was no significant association between BMI and survival.³⁹

Association with chemotherapy toxicity

Several studies have examined the associations between chemotherapy toxicity and body composition in early stage breast cancer. In the largest study published to date, low skeletal muscle index measured by CT was associated with a higher risk of any grade 3/4 toxicity (p=0.0002) among 151 non-metastatic breast cancer patients receiving anthracycline and taxane based chemotherapy. In addition, low skeletal muscle gauge (SMG) (skeletal muscle index multiple by skeletal muscle radiodensity) was associated with a higher risk of grade 3/4 hematologic toxicity (RR=2.12; 95% CI=1.11–4.04), grade 3/4 gastrointestinal toxicity (RR=6.49; 95% CI=1.42–29.63) and hospitalization (RR=1.91; 95% CI=1.00–3.66), even after adjusting for age and body surface area.⁴⁰ Among 84 Asian breast cancer patients with non-metastatic breast cancer, higher levels of visceral fat was associated with a higher risk of grade 4 leukopenia (p=0.014), whereas lower skeletal muscle index was associated with a trend towards a higher rate of grade 3/4 leukopenia and neutropenia (p=0.051).⁴¹ A smaller earlier study of 24 stage II–III breast cancer patients treated with epirubicin based chemotherapy found that lower lean body mass was associated with higher risks of toxicity with differences in pharmacokinetics.⁴² In combination, these studies suggest that measures of body composition are better predictors of chemotherapy related toxicity than the widely used body surface area. However, none of these studies have looked at the efficacy of chemotherapy dosing based upon body composition parameters.

Intervention studies on body composition among breast cancer patients

In addition to being an important prognostic factor, body composition is also a potentially modifiable risk factor. Several trials have successfully demonstrated this approach in non-metastatic breast cancer patients. The largest study was a multicenter randomized trial of 200 subjects who were randomized to usual care (n=60), aerobic exercise training (n=64), or resistance exercise training (n=66) for the duration of adjuvant chemotherapy. Resistance training was more likely to increase skeletal muscle index and reverse sarcopenia than either usual care or aerobic exercise. Improvement in sarcopenia was also associated with a clinically meaningful improvement in quality of life and fatigue.⁴³ Another randomized trial compared a combined aerobic and resistance exercise program versus usual care among 121 breast cancer survivors taking aromatase inhibitors and reported significant increases in lean body mass and decreases in body fat over 12 months.⁴⁴ Finally, in an exploratory study, 20 subjects were randomized to either a 16 week aerobic and resistance training program versus delayed control. Exercise participants experienced significant improvements in lean body mass, percent body fat, and fat mass. Inflammatory biomarkers and adipose tissue were examined at baseline and at end of intervention and also showed significant improvement in markers of inflammation with exercise.⁴⁵

Conclusion/future directions

Even among non-metastatic cancer patients, sarcopenia is highly prevalent. With the wide use of CT scans in cancer staging and diagnosis and the availability of software to automate the process, assessments of body composition should be incorporated as part of routine clinical assessments for patients with early stage breast cancer and colorectal cancer given the strong associations with chemotherapy toxicity and complications and most importantly both disease-free and overall survival. Further research should also focus on deriving clinical cutpoints for sarcopenia that will help to shape clinical care. Body composition measures can be a stronger predictor of surgical complications than body mass index or weight and should be considered as part of pre-operative risk management. Body composition is strongly associated with chemotherapy toxicity and studies should be done in the metastatic setting to look at the efficacy of dosing based upon lean body mass since the goal of chemotherapy in the metastatic setting is palliative and not curative. Body composition is a modifiable factor, as has been shown in multiple randomized trials, and should be considered when designing both nutritional and physical activity interventions for cancer survivors.