Pre‐rehabilitation interventions for patients with head and neck cancers: A systematic review and meta‐analysis

To investigate the effect of pre‐rehabilitation interventions such as nutrition and exercise for patients with head and neck cancer (HNC).

ups and larger sample sizes, and investigations comparing nutritional supplements with exercise programs are needed.

K E Y W O R D S
cancer, exercise, head and neck, nutrition, pre-rehabilitation

| INTRODUCTION
Head and neck cancers (HNCs) are a group of malignancies that arise from the nasal and oral cavities, pharynx, larynx, paranasal sinuses, and salivary glands. 1 The mainstay of treatment for localized disease is surgery. 2 However, a common consequence of HNC surgery is malnutrition secondary to poor oral intake.Multiple complications contribute to poor oral intake, including dysphagia, odynophagia, dry mouth, and anatomical disruption. 2,3Consequently, many patients suffer weight loss, muscular atrophy, poor functional status, and reduced quality of life (QoL).
Prehabilitation is a term that refers to interventions that aim to improve the physical and mental condition of patients with cancer before they undergo treatment.However, there is no consensus on the definition and scope of prehabilitation among researchers and practitioners.Some may consider prehabilitation as a single session or a short-term program that takes place before the initiation of cancer treatment, while others may view it as a continuous or intermittent process that spans different phases of treatment.Similarly, some may focus on specific components of prehabilitation, such as providing information, teaching stretches, or prescribing exercises, while others may adopt a comprehensive approach that incorporates multiple elements.][4] To minimize the risk of long-term malnutrition, optimizing perioperative health through pre-rehabilitation ("prehabilitation") programs is an area of interest in surgical oncology. 4Multimodal biopsychosocial interventions have been explored, where baseline functional, physical, and psychological health statuses are assessed.The patient undergoes an assessment to identify any areas of weakness or impairment that may affect their ability to function optimally.Based on the results of the assessment, the patient receives appropriate interventions that aim to improve their physical and mental condition before they start their cancer treatment. 4,5Studies in other cancer populations such as lung, gastrointestinal, and prostate have shown that this approach improves outcomes compared with non-prehabilitation populations. 6These promising results have inspired a surge of similar literature exploring prehabilitation in patients with HNCs. 7ostoperative dysphagia impairs nutritional intake and physical function after HNC surgery.Therefore, optimizing preoperative nutritional status and exercise capacity are key targets for prehabilitation.Preventing or reducing weight loss and catabolism can maintain strength, energy levels, and QoL. 8 The evidence so far has shown that nutritional counseling and/or oral supplementation is associated with improved outcomes and QoL compared with controls. 9,10espite promising preliminary results, there is an overall paucity of evidence surrounding the impact of prehabilitation in HNC.A recent meta-analysis examining the effect of exercise and nutrition interventions during HNC radiotherapy suggested an improvement in physical function, but no effect on nutritional status. 2 In addition, existing review articles on rehabilitation for HNC focus on the post-treatment setting, and do not explore pre-rehabilitation. 2,7Therefore, this systematic review and meta-analysis sought to examine the effect of pre-rehabilitation (i.e., optimizing nutritional status and physical activity before curative treatment) on patients with HNC and make recommendations on the optimal prehabilitation program for patients with HNC.

| MATERIALS AND METHODS
2][13] The study was registered on the International Prospective Register of Systematic Review (PROSPERO; CRD42023394284).

| Literature search
Our search was performed until December 2022 through four main databases: PubMed, Web of Science, Cochrane Library, and Scopus.The following search strategy was used: (((pre-rehabilitation OR prophylactic OR preventative OR pretreatment OR prehab OR perioperative OR prevention OR preservation OR prevent OR Rehabilitation OR "Pre-treatment") AND (exercis* OR diet OR diets OR nutrition* OR training OR "physical activity" OR "diet therapy" OR "dietary intake" OR Dietary OR Nutritional)) AND ("Head and neck cancer" OR Oropharyngeal OR HNC OR "Throat cancer" OR "Oral Cancer")).

| Studies selection and eligibility criteria
All studies (RCTs, non-RCTs, and observational studies) that met the following criteria were considered: (1) patients with HNC treated with either surgery and/or radiotherapy; (2) were part of exercise, nutrition, or psychiatric programs within the study and the eligible treatment restricted to those that started before cancer treatment with or without they continued the prehabilitation program during the treatment but not after cancer treatment; (3) were part of prehabilitation interventions such as control or placebo group; (4) outcomes assessed by the study included one or a combination of the following: weight loss, complication rate, mucositis rate, mortality rate, change in the maximum of mouth opening, length of hospital stay, dysphagia, body mass index, admission rate, EORTC QLQ-C30 functional scale scores (Cognitive, Emotional, and Physical), and EORTC QLQ-C30 symptom scale scores (Appetite loss, Dyspnea, Fatigue, Pain, Swallowing, and Trouble with social eating).After searching, we removed duplicates using End-Note software.Screening for relevance was undertaken by two authors by screening for titles and abstracts, then full-text.To identify any missed relevant articles, we manually screened the references of the included studies.If any conflicts were encountered, decisions were settled by a third author.

| Quality assessment
The quality of RCTs was evaluated using the Cochrane risk of bias tool (version 1). 14The following domains make up this tool: (1) detection selection bias and other biases; (2) allocation of arms; (3) participant and investigator blinding; (4) assessment of outcomes and their blinding; and (5) randomization of the population.The possibility of bias in judgment can be a high, low, or ambiguous risk of bias.The quality of cohort, crosssectional, and case-control studies were assessed using the National Institutes of Health risk of bias tool for each study design. 15These are composed of questions about population and sample size justification, the research question, control definition, inclusion criteria and cases, event time, blindness, and the reporting of confounders.The overall quality of the included studies was categorized as high, fair, and low quality.

| Data extraction
Data were extracted into Excel spreadsheets and contained the following items: (1) summary of characteristics including study design, description of the intervention, inclusion criteria, primary outcomes/endpoint, and conclusion; (2) baseline data including author and year, study arms, sample size, age, follow-up duration, and type of intervention; (3) outcomes including weight loss, serious complications rate (surgical site infection, pneumonia, postoperative bleeding, pharyngeal leak or fistula, and others complications according to each study), mucositis rate, mortality rate, maximum mouth opening change, length of hospital stay, dysphagia rate, body mass index, admission rate, EORTC QLQ-C30 (cognitive, emotional physical, appetite loss, dyspnea, fatigue pain, swallowing trouble with social eating).

| Data synthesis
Continuous data were reported as mean difference (MD) and 95% confidence interval [95% CI].Categorical variables were reported as risk ratio (RR) and 95% CI.Heterogeneity was assessed by the I-square (I 2 ) statistic and the chi-square test; data was considered heterogeneous if the p-values of the chi-square were <0.1 and the I 2 value was above 50%.Homogeneous data was analyzed using a fixed-effects model, while heterogeneous data was analyzed using a random effects model.Review Manager [RevMan] v5.4 was used to conduct all statistical and meta-analyses, A p-value of <0.05 was considered statistically significant.

| Literature search and study selection
Initially, 8646 studies were identified, this was reduced to 5495 after the removal of duplicates.Following title and abstract screening, 133 studies proceeded to full-text screening.Of these, 46 studies satisfied our inclusion criteria-31 articles presented quantitative data and 15 presented qualitative evidence (Figure 1 shows the PRISMA flowchart).

| Characteristics of the included studies
We included 24 RCTs, 14 cohort studies, 7 case-control studies, and 1 cross-sectional study.The type of prehabilitation programs used were 29 studies used different types of exercises (8 of them had specific swallowing prehabilitation exercise), 16 of them used nutrition (most of the studies used an enriched formula either enriched with arginine or eicosapentaenoic acid [EPA]), and finally only 1 study used psychoeducational intervention.Also, the average duration of the prehab program differs from study to study but the daily dose of exercises recommended ranged from 30 to 440 repetitions a day according to Loewen et al. 7 The baseline characteristics of included studies are summarized in Table 1.
The RCTs had a moderate risk of bias, the domain with the highest risk of bias was participants' blinding while most studies have a low risk of bias regarding selective reporting and incomplete data domains (Figure 2), and cohort and case-control studies were of fair to good quality, the domain with the highest risk of bias was also blinding of the outcome assessors, and key potential confounding variables if they were measured and adjusted statistically or not.Meanwhile, most of the domains have a low risk of bias such as the research question, the study population, and the rate of eligible persons (Data S1 and S2, Supporting Information, respectively).

| Qualitative synthesis
In Ajmani et al. and Virani et al., 16,17 a proactive swallowing rehabilitation program was effective in increasing quality of life and decreasing the risk of feeding tube use.Carmignani et al. 18 identified that purposeful swallowing behaviors could reduce the rate of dysphonia and dysphagia in the long and short term.Reduction in dysphagia following a swallow preservation protocol was also reported by Kulbresh et al. 19 and Peng et al. 20 Cnossen et al. 21found adherence to exercise performance in the first 6 weeks was higher than in the last 6 weeks for patients treated with chemotherapy in combination with swallowing-sparing intensity modulated radiation therapy.Hadju et al. 22 identified that home-based preventive swallowing exercises improved quality of life.In their study, eating and exercising during radiotherapy or chemoradiotherapy was crucial for maintaining normal dietary habits.Retel et al. 23 described their preventive exercise program as a cost-effective measure for improving QoL for patients with HNC.Finally, van der Molen et al. 24 showed that the implementation of daily prophylactic exercises was as effective as a formal pretreatment rehabilitation program in minimizing the impact of chemotherapy on QoL.

| DISCUSSION
The main aim of our study was to investigate the effects of prehabilitation exercise, nutrition, and psychoeducational effects on patients with head and neck cancer (HNC).Our results showed that the prehabilitation of patients with HNC significantly decreased mortality rate, serious complication rate, dysphagia rate, and length of hospital stay.Also, it was associated with a significant decrease in weight loss and showed promising effects.
One of the main signs of HNC is weight and BMI loss secondary to dysphagia and/or odynophagia.This occurs secondary to anatomical disruption of structures involved in the swallowing reflex-culminating in poor oral intake. 25Moreover, treatment with radiation and chemotherapy also contributes to a loss in appetite and body weight. 26Thus, weight control is an important predictor of long-term outcomes and mortality in patients with HNC, and ensuring adequate nutritional intake is a priority.The patients that were applied to the prehabilitation exercise program showed no significant improvement in the weight loss outcome especially in short terms, as the ability to chew and swallow is still missed for patients, on the other hand, we can find a significant decrease in the weight loss in the included studies depending on the nutritional intervention.Especially the early nutritional intervention. 27Moreover, we should mention the poor results of the exercise-based programs in weight loss outcomes could be due to the heterogeneity across the included studies.While HNC interventions vary among studies, the importance of being able to correct, and maintain the ability to chew and swallow remains a constant to ensure optimal oral intake.Because of persistent barriers to normal eating behaviors, nutritional support needs to be considered pre-interventionally as well as following treatment. 28ysphagia is a relatively common and serious complication of chemotherapy for HNC.It results in malnutrition, weight loss, and potentially fatal aspiration pneumonia.
Swallowing dysfunction during chemoradiotherapy (CRT) is associated with worsened QOL, psychological stress, and poorer prognosis. 29Only exercise-based interventions were effective for dysphagia.On the other hand, the nutrition-based interventions were of no significant benefit to the incidence of dysphagia.This is likely because the root cause of dysphagia is neuromuscular and can be modified by repetitive purposeful swallowing rather than nutrition.Preventing dysphagia is pertinent to maintaining oral intake.Therefore, exercise programs should coincide with nutritional support programs, to give patients the best outcome.
Prehabilitation nutrition significantly reduced the rate of serious complications.One explanation is that nutritional supplements contain essential amino acids arginine and glutamine, which the body cannot naturally produce.In post-traumatic conditions, arginine and glutamine are crucial for supporting the immune system and promoting tissue repair. 30,31Daily allowances of arginine and glutamine are 5-6 and 1 g, respectively.Studies supplementing at this level suggest that prehabilitation nutrition is important to address deficits and provide the surplus needed in preparation for impending insults. 32,33utritional support and psychoeducation significantly reduced the overall mortality rate.However, for this analysis, only two studies were included; with performance heavily weighted toward Malik et al. 34 The psychoeducational model seeks to integrate disease-and treatmentspecific knowledge into the program to better understand patients' emotional and motivational states.Psychoeducational interventions are already known to decrease the incidence of death in patients with breast cancer. 35he potential mechanism is that psychoeducation promotes patient adherence to treatment and supports a positive mindset following treatment.Another meta-analysis of psychosocial intervention in patients with all cancers suggests that there were survival benefits at the 1-year mark. 36In our sample, Ohba et al. showed that patients who received psychoeducation had a shorter LOS after HNC surgery, suggesting that there is also a short-term benefit. 37ur meta-analysis should be considered in the context of the following limitations.First, it is difficult to recommend a specific prehabilitation program or comment on the effectiveness of specific components as the included studies were underpowered and had unclear methodology.Second, many outcomes were not assessed in adequate numbers to estimate statistical certainty.For example, outcomes of functional status, appetite loss, dyspnoea, and fatigue were only measured by two studies.Third, many meta-analyses had heterogeneity that could not be resolved.This may impair the generalizability of our results.Moreover, we could not assess the different timeframe results during the follow-up and their impact on our results due to the limited data from our included studies.Lastly, most of the included studies were from largely Caucasian or European populations.Therefore, the results may not be generalizable across cultures and ethnicities.Nonetheless, this study provides statistical support for the use of prehabilitation in HNC.Future studies should include larger, multi-ethnic populations and compare individual interventions to determine the optimal prehabilitation program.Also, we need to conduct high-quality trials conducted on that topic taking into consideration mentioned confounders that could bias the results.

| CONCLUSIONS
Prehabilitation programs that involve exercise, nutrition, or psychoeducation have shown potential benefits for enhancing the quality of life and reducing the mortality and morbidity of patients with HNC after treatment.However, the evidence is limited by the heterogeneity and inconsistency of prehabilitation practices across studies.Future research should address the challenges and gaps in defining, implementing, and evaluating prehabilitation interventions, such as the timing, duration, content, and outcome measures of prehabilitation.It is also important to explore the comparative effectiveness of different types of nutritional supplements or exercise programs for prehabilitation.A more standardized and comprehensive approach to prehabilitation research would facilitate the translation of evidence into clinical practice and improve the outcomes of patients with HNC.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was prospectively registered with PROSPERO, the international prospective register of systematic reviews (registration no.CRD42023394284).

F I G U R E 2
Risk of bias graph summary for randomized controlled trials [Color figure can be viewed at wileyonlinelibrary.com]

F I G U R E 3
Forest plot of weight loss (kilograms) [Color figure can be viewed at wileyonlinelibrary.com]F I G U R E 4 Forest plot of length of hospital stay (days) [Color figure can be viewed at wileyonlinelibrary.com]F I G U R E 5 Forest plot of incidence of serious complications rate [Color figure can be viewed at wileyonlinelibrary.com]F I G U R E 6 Forest plot of mortality rate [Color figure can be viewed at wileyonlinelibrary.com]À0.83,6.22, p = 0.13), and results were homogenous (p = 0.51, I 2 = 0%) (FigureS3).
Summary of included studies in this systematic review and meta-analysis 1 PRISMA flow chart of selected studies [Color figure can be viewed at wileyonlinelibrary.com]TABLE 1 T A B L E 1 (Continued) T A B L E 1 (Continued) T A B L E 1 (Continued) T A B L E 1 (Continued)better weight retention (2.55; 2.27, 2.82, p < 0.00001), and results were homogenous (p = 0.11, I 2 = 36%; Figure3).