Pre-operative sarcopenia as reflected by computed tomography predicts post-operative complications in patients undergoing total laryngectomy for head and neck cancer: a systematic review and meta-analysis

Introduction

Head and neck cancers are one of the most common malignancies worldwide (1). Of these, laryngeal and hypopharyngeal tumours account for approximately 1% and 0.4% of cases, respectively (1). For patients with these cancers, total laryngectomy (TL) with adjuvant (chemo)radiotherapy is often the approach for curative-intent treatment of advanced tumours. TL can also be considered as salvage treatment for those with local recurrences after organ preserving primary treatment (2). Importantly, complications may arise following TL, including pharyngocutaneous fistula (PCF) formation, wound dehiscence, flap loss, infection, dysphonia, and dysphagia, all of which can lead to functional aerodigestive disorders (3). Furthermore, due to the location of these tumours, weight loss and malnutrition are highly important considerations when it comes to peri-operative optimisation and recovery.

Sarcopenia is defined by the European Working Group on Sarcopenia in Older People (EWGSOP) as the combination of low muscle mass and quality as assessed by computed tomography (CT) or magnetic resonance imaging (MRI) and of low muscle strength as assessed by grip strength and chair stand test (4). When considering weight loss and malnutrition, sarcopenia has gained increasing recognition as an important prognostic factor for head and neck malignancies (5-9). Despite this, the methods for determining sarcopenia are highly heterogeneous, with multiple approaches of evaluation including CT or MRI, functional assessments, biochemical measurements (e.g., through urinary creatinine), and anthropomorphic bioimpedance measurements (10,11). The lack of a standardised method for sarcopenia evaluation impedes its validation as a reliable marker for predicting patient outcomes following TL.

With regard to the pre-operative assessment of patients suitable for TL, the majority will undergo CT or MRI, thus presenting an opportunity to incorporate the assessment of a key aspect of sarcopenia, i.e., muscle mass loss, into peri-operative risk stratification. The impact of sarcopenia on post-operative and oncological outcomes for patients with head and neck cancer undergoing TL remains poorly characterised, with the vast majority of literature exploring head and neck cancers and the various operative options as a group. This systematic review seeks to evaluate the role of sarcopenia as reflected by CT on the outcomes for patients undergoing TL.

Methods

Search protocol and registration

This review was performed in adherence to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (12) (available at https://www.theajo.com/article/view/10.21037/ajo-24-72/rc). The review protocol was prospectively registered in the PROSPERO database (PROSPERO ID: CRD42023463261).

Literature search strategy

A computer-assisted literature search was conducted on Medline, Embase and Google Scholar databases on 12 September 2023. Hand-searching was utilised to identify additional relevant articles from the reference lists of captured studies from the search. The search strategy combined medical subject headings (MeSH) and keywords related to sarcopenia, laryngeal cancer, post-operative complications and survival. Truncations and Boolean operators were used during the search to find all relevant articles.

Inclusion and exclusion criteria

Peer-reviewed academic publications available in full-text and in English language which evaluated the prognostic role of pre-operative radiologically-confirmed sarcopenia on post-operative and oncological outcomes following TL for head and neck cancers were considered.

Articles were included if they were: (I) original and peer-reviewed randomised-controlled trials, prospective non-randomised trials, retrospective non-randomised trials and, non-randomised observational studies; (II) papers that included adults aged 18 years or older with head and neck cancer and evaluated for sarcopenia with cross-sectional radiological approaches (CT or MRI) before TL; (III) papers that utilised CT or MRI area or density-based measurement methods including skeletal muscle index (SMI), psoas muscle index (PMI), total psoas index (TPI), total psoas area (TPA), total abdominal muscle area or skeletal muscle density (SMD); (IV) evaluating endpoints of interest including post-operative outcomes and oncological (survival) outcomes.

Articles were excluded if they were: (I) of the following study designs and types; systematic reviews, meta-analyses, non-human studies, preclinical studies, conference papers, letters, editorials, opinion articles, comments, case reports or case series; (II) had incomplete data; (III) evaluated sarcopenia by other methods such as skinfold thickness testing, arm or torso circumference testing, total body potassium levels or daily urinary creatinine output; (IV) included only patients with metastatic laryngeal cancer; (V) included patients who underwent head and neck cancer resection that was not TL; (VI) included patients who solely underwent non-surgical treatment including radiotherapy, chemotherapy, immunotherapy or a combination of these modalities; (VII) included only paediatric populations.

Literature screening

Screening by title and abstract was performed by two independent investigators (E.C., K.V.). Titles and abstracts that did not provide sufficient information progressed to full-text analysis. The same two investigators then independently performed a full-text analysis based on the eligibility criteria. Disagreement during this process was resolved by consensus. If consensus was not achieved, a third independent investigator (K.D.R.L.) was consulted to finalise the decision.

Outcomes

The primary outcomes of interest included post-operative outcomes including total post-operative complications, severe complications (Clavien-Dindo 3–5), cardiopulmonary complications, anastomotic leak, wound complications (consisting of dehiscence, seroma, chyle leak and infection), total infections, PCF formation, length of stay [total hospital and intensive care unit (ICU)], readmission, return to theatre, dysphagia or stenosis or stricture, bleeding or haematoma, death (30-day mortality and total mortality) and oncological outcomes including overall survival, cancer-specific survival and progression/disease-free survival.

Secondary outcomes of interest included swallowing function, quality of life and psychological comorbidities following surgery.

Data extraction

Studies included in this review were extracted for data including study name, author, year of publication, study design, country of publication and demographic data of study cohorts (age, sex, total number of patients) and data relevant to our outcomes of interest. In papers with insufficient information on evaluated head and neck cancer surgery as a group, corresponding authors were contacted to obtain data specific to eligibility criteria and outcomes of interest.

Quality and risk of bias assessment

Articles were assessed for methodological quality using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool by two independent investigators (E.C., K.V.) (13). Disagreement during this process was resolved by consensus. If consensus was not achieved, a third independent investigator (K.D.R.L.) was consulted to finalise the decision. Publication bias was assessed with a funnel plot as part of the statistical analysis of included articles if sufficient number of publications (>25) was available.

Statistical analysis

Statistics analysis was performed utilising Review Manager 5.4 (RevMan 5.4) (Cochrane, London, United Kingdom). Odds ratio (OR), hazards ratio (HR) and their 95% confidence intervals (95% CIs) were extracted from the included studies and meta-analysed if there was homogeneous data. In the absence of homogeneous data, descriptive results were presented. Continuous data whenever relevant were converted to single measures of effect, such as from median and interquartile range to mean and standard error utilising the Wan method (14).

Heterogeneity between studies was evaluated with the Higgins I² test (15). Values of I² at 25%, 50%, and 75% were graded as low, moderate and high heterogeneity, respectively. A fixed-effects model was used if substantial heterogeneity was absent and a random-effects model if substantial heterogeneity was found. A P value of <0.05 was considered to be statistically significant. To determine sources of heterogeneity, subgroup analyses and meta-regression analyses whenever relevant were performed.

Subgroup analyses

Subgroup analysis of relevant factors including the presence or absence of obesity (as defined by body mass index) and age above or below 70 years were planned.

Certainty of evidence

Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.

Results

Literature search

A total of 305 peer-reviewed articles were identified following the literature search. A further 7 articles were identified from hand-searching of relevant reference lists of captured articles. After accounting for duplicate entries, 221 articles progressed to screening by title and abstract. Based on inclusion and exclusion criteria, 187 articles were excluded and 34 articles progressed to full-text analysis. Four articles were eligible for inclusion into this review. The PRISMA flowchart of the literature search is shown in Figure 1. The search query can be viewed in the supplementary file (Appendix 1).

Figure 1 Literature search and article selection as represented through the PRISMA flowchart. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Overview of included studies and patient characteristics

An overview of included studies is presented in Table 1. A total of 4 studies encompassing 475 patients were included (16-19). Of these, 405 were male and 70 were female. All included studies were of retrospective cohort study design and were published from 2017. Overall, the pooled cohort of patients included 218 with sarcopenia and 257 without sarcopenia. The pooled mean age, body habitus metrics, cancer location, primary tumour T stage, cancer tumor-node-metastasis (TNM) stage, surgical approaches and presence of adjuvant or neoadjuvant chemotherapy and/or radiotherapy was not able to be adequately calculated given missing data.

Methods of sarcopenia determination

Sarcopenia was determined by high-modality cross-sectional imaging (CT or MRI) in all included studies (Table 2). The predominant method of sarcopenia determination was using CT at the level of the lumbar vertebra 3 (L3) to calculate skeletal muscle mass as represented by SMI (n=3, 75%). One article utilised similar metrics albeit with CT at the level of cervical vertebra 3 (C3) (n=1, 25%). The papers either referenced Prado et al. or Swartz et al. for methodologies guiding sarcopenia determination (20,21).

Post-operative outcomes

All included studies reported on post-operative complications following TL.

Total post-operative complications

All included studies analysed the presence of total post-operative complications following TL (16-19). A random-effects model was employed to compare sarcopenic to non-sarcopenic patients. The pooled analysis of 475 patients (218 sarcopenic, 257 non-sarcopenic) demonstrated that there was evidence to suggest that sarcopenia is a prognostic factor for total post-operative complications (OR 2.29, 95% CI: 1.05–4.97, P=0.04, I²=66%) (Figure 2A).

Figure 2 Meta-analysis of post-operative outcomes when comparing sarcopenic to non-sarcopenic patients undergoing total laryngectomy. (A) Forrest plot employing a random-effects model to evaluate sarcopenia compared to non-sarcopenia and rates of total post-operative complications following total laryngectomy. (B) Forrest plot employing a random-effects model to evaluate sarcopenia compared to non-sarcopenia and rates of wound complications following total laryngectomy. (C) Forrest plot employing a random-effects model to evaluate sarcopenia compared to non-sarcopenia and rates of pharyngocutaneous fistula formation following total laryngectomy. (D) Forrest plot employing a random-effects model to evaluate sarcopenia compared to non-sarcopenia and length of stay following total laryngectomy. Blue boxes (A-C) indicate dichotomous variables and green boxes (D) indicate continuous variables. CI, confidence interval; SD, standard deviation.

Wound complications

Two studies analysed the presence of wound complications following TL (16,19). A random-effects model was employed to compare sarcopenic to non-sarcopenic patients. The pooled analysis of 154 patients (91 sarcopenic, 63 non-sarcopenic) demonstrated that there was little to no evidence to suggest sarcopenia is a prognostic factor for wound complications (OR 1.97, 95% CI: 0.18–21.19, P=0.58, I²=84%) (Figure 2B).

PCF

Three studies analysed the presence of PCF formation following TL (17-19). A random-effects model was employed to compare sarcopenic to non-sarcopenic patients. The pooled analysis of 405 patients (164 sarcopenic, 241 non-sarcopenic) demonstrated that there was very strong evidence to suggest sarcopenia is a prognostic factor for PCF formation (OR 2.28, 95% CI: 1.45–3.59, P=0.0004, I²=0%) (Figure 2C).

Length of stay

Three studies analysed the duration of length of stay following TL (17-19). A random-effects model was employed to compare sarcopenic to non-sarcopenic patients. The pooled analysis of 319 patients (146 sarcopenic, 173 non-sarcopenic) demonstrated that there was no evidence to suggest sarcopenia leads to prolonged length of stay (OR 2.30, 95% CI: −4.37 to 8.98, P=0.50, I²=72%) (Figure 2D).

Other outcomes

Pooled analysis was not possible for other outcomes of interest as identified a priori. Bril et al. demonstrated that the presence of sarcopenia was associated with a slightly higher proportion of severe post-operative complications as defined by a Clavien-Dindo score of 3 or above (sarcopenia: 34.86%, non-sarcopenia: 24.60%; P=0.11), 30-day mortality (sarcopenia: 3.67%, non-sarcopenia: 0%; P=0.05) and overall mortality (sarcopenia: 73.83%, non-sarcopenia: 43.65%; P<0.01) (17). Salati et al. highlighted that sarcopenia similarly led to a higher proportion of post-operative infections (sarcopenia: 16.22%, non-sarcopenia: 8.51%; P=1.0) and rates of return to theatre (sarcopenia: 40.54%, non-sarcopenia: 38.30%; P=1.0) (19). This effect however was not observed for post-operative bleeding (sarcopenia: 0%, non-sarcopenia: 4.26%; P value not reported) (19). There were no data available for other a priori post-operative outcomes of interest including cardiopulmonary complications, anastomotic complications, length of ICU stay, readmission, dysphagia, stenosis, stricture, quality of life, swallowing function and psychological comorbidities.

Oncological outcomes

Pooled analysis was not possible for the oncological outcomes identified a priori. Despite this, Bril et al. highlighted that sarcopenia was associated with poorer survival when compared to non-sarcopenic counterparts (HR 1.849; 95% CI: 1.202–2.843; P<0.001) (17). There were no data available for other a priori oncological outcomes of cancer-specific survival or progression/disease-free survival.

Quality and risk of bias assessment

A risk of bias assessment was performed on the included studies utilising the ROBINS-I tool (Figure 3). Overall, all articles were at moderate risk of bias. Key areas that introduced bias were related to missing data in the form of exclusion due to the absence of CT. Additionally the presence of male only cohorts and exclusion of patients with CT performed outside of a specific timeframe were other sources of potential bias. Publication bias was not assessed given the low number of included articles.

Figure 3 Risk of bias assessment utilising the ROBINS-I tool. ROBINS-I, Risk Of Bias In Non-randomised Studies of Interventions.

Discussion

This systematic review and meta-analysis indicates that pre-operative sarcopenia, as reflected by CT, is a negative prognostic factor for post-operative complications of TL. This finding however is made with low certainty following GRADE assessment of outcomes attributable to clinical heterogeneity of included studies and inconsistency in findings (Table 3). The observation is relevant to patients and surgeons in making informed decisions on managing advanced laryngeal cancer and other head and neck cancers requiring a TL.

Based on a foundation of four studies considered by us as at low to moderate risk of bias, the principal finding of our analysis is that sarcopenia as reflected by CT is a prognostic indicator of total post-operative complications and PCF formation following TL for head and neck cancer. The fact that other a priori outcomes do not emerge as associated with sarcopenia is likely due to the low number of patients available for the meta-analysis. Our observation underscores the individual conclusions of Achim et al., Bril et al. and Casasayas et al. and adds to emerging evidence of the benefit of utilising sarcopenia in predicting post-operative outcomes (16-18). For a general comparison, patients with sarcopenia subjected to colorectal surgery featured poor 30-day and 1-year mortalities, and for elderly patients undergoing abdominal surgery it was a predictor of a high 90-day mortality (22-24).

To the best of our knowledge, this is the first systematic review and meta-analysis performed to explore the role of sarcopenia as reflected by CT on outcomes following TL. We acknowledge that some limitations of the analysis must be considered. In particular, the four publications selected for analysis were retrospective observational studies with marked inter-study heterogeneities concerning sample size, male-to-female proportions, types of cancers involved, extent of neck dissection performed, extent of previous chemoradiotherapy given, and methods of sarcopenia determination. Furthermore, they comprise imaging data but no information on muscle strength, the combinations of which now may be regarded as gold standard for the diagnosis of sarcopenia. Also, besides these publications, six additional ones, all likely relevant from a clinical perspective, were excluded during the screening process due to a lack of retrievable data. Efforts were made to contact the authors of these articles without success. Furthermore, the inclusion of Bril et al. in this meta-analysis is associated with the incorporation of MRI data into evaluation of sarcopenia and outcomes following TL. MRI represents cross-sectional imaging with a higher resolution compared with CT, which was deemed appropriate for this review but was therefore not considered an a priori exclusion. Taken together, further studies, preferably prospective and including the assessments of muscle strength in addition to imaging, are warranted focusing on the importance of sarcopenia to the outcome of cancer treatment.

Following our careful assessment of the four publications selected for this systematic review and meta-analysis, we considered additional post-hoc analyses to explore aspects of confounders and data heterogeneity, respectively. Arguably, by removing studies considered to be at high risk of bias, omitting male-only studies, and considering confounders such as presence or absence of free-flap reconstruction or presence or absence of prior chemotherapy and/or radiotherapy, the potential confounders of methodological rigour and high male representation for the outcomes following TL may be reduced or avoided. Similarly, by specific a priori subgroup analyses, e.g., obesity vs. non-obesity and age above vs. below 70 years, aspects of heterogeneities may be considered. However, due to a paucity of data in the publications (or available through the corresponding authors), such analyses were impossible to perform. Inferentially, additional controlled studies are warranted involving a number of patients great enough to perform also necessary subgroup analyses.

In the 34 retrieved studies as a whole, we expectedly found marked heterogeneities in the way sarcopenia was defined. For example, some studies explored scoring systems such as the “Strength, assistance with walking, rising from a chair, climbing stairs, and falls” (SARC-F) index, while others utilized the “Fat-free mass index” (25). Functional assessments were also performed albeit with variable results, likely due to a reliance on subjective reporting (26). Lately, there has been a shift to the use of CT, and to some extent MRI, as a standardizable method of evaluating muscle mass when sarcopenia is suspected. On examining the selected four studies, our review showed that cross-sectional CT imaging was a feasible alternative. For example, Achim et al. defined sarcopenia by SMI through CT available as part of a standardised work-up (16). Similarly, Bril et al. utilised cross-sectional imaging at the C3 level, gained during the regular pre-operative assessment, to define sarcopenia.

While sarcopenia is under-recognised in head and neck cancer populations, pre-operative identification of the condition may provide an opportunity to optimise patients and improve outcomes post-surgery. However, there is a lack of evidence-based strategies to address sarcopenia. Available evidence suggests that multi-disciplinary multimodal prehabilitation may halve the rate of post-operative complications, improve psychological well-being, and confer non-health benefits, but there is no consensus on what such programs may include (27-29). In this context, the literature emphasises physical therapy to build and maintain skeletal muscle mass to prevent, delay, and potentially reverse sarcopenia (4,30). Also, there is evidence of the role of goal-oriented nutrition; enterogastric nutrition is a key aspect of the care of head and neck cancer patients, for example for those who develop dysphagia in neoadjuvant chemoradiotherapy settings (31). Sarcopenia research additionally identifies the role of specific diets, particularly those rich in amino acids such as glutamine, L-arginine, and leucine, in improving sarcopenic states (32,33).

In head and neck cancer, time constraints are an additional issue, with arguments that the time required for prehabilitation is not acceptable concerning the evident progress of the underlying oncological process. However, the current literature suggests that multidisciplinary, multimodal prehabilitation can effectively be delivered within a period of 4–8 weeks and therefore can be considered for peri-operative surgical and oncological programs (34). Our meta-analysis highlights that, in light of the prognostic significance of sarcopenia and the high feasibility of sarcopenia determination in the pre-operative setting, there is a role for considering sarcopenia evaluation, and its treatment, as part of a prehabilitation program for patients undergoing TL for head and neck cancer. Besides physical training, such programs may also comprise flexibility and balance exercises as well as nutritional intervention. If future prospective studies can establish a correlation between prehabilitation for sarcopenia and a reduction in adverse outcomes, it will likely lead to the development of an evidence-based framework leading up to TL.

Conclusions

This meta-analysis demonstrates that pre-operative sarcopenia, as reflected by CT, is a significant prognostic factor for the development of post-operative complications and PCF for head and neck cancer patients undergoing TL. The finding raises ideas concerning the consideration of routine sarcopenia assessment in the pre-operative setting, particularly given that CT imaging is routinely performed in the workup of patients offered TL. Arguably, these findings also highlight the potential role of multidisciplinary multimodal prehabilitation regimens in the optimisation of these patients. However, the evidence for this remains poorly characterised because of data that are mainly derived from retrospective observational studies of small sample sizes with marked clinical heterogeneity.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://www.theajo.com/article/view/10.21037/10.21037/ajo-24-72/rc

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-24-72/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-24-72/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The review protocol was prospectively registered in the PROSPERO database (PROSPERO ID: CRD42023463261).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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