Multimodal intervention for sarcopenia in nasopharyngeal carcinoma patients undergoing definitive treatment: a pilot randomized controlled trial protocol

Abstract

Background

This protocol describes a pilot randomized controlled trial (RCT) designed to assess the feasibility of a multidisciplinary, multimodal intervention for sarcopenia prevention in patients with nasopharyngeal carcinoma (NPC) undergoing concurrent chemoradiotherapy (CCRT). The intervention was developed using the Medical Research Council (MRC) framework and incorporates personalized immunonutrition, structured exercise, side effect management, behavior monitoring, and guidance. This pilot trial aims to evaluate the feasibility of implementing a multimodal intervention model in this patient population.

Methods

This study will be a single-site RCT including 30 patients with NPC undergoing definitive treatment. The trial will be conducted from September 2025 to May 2026 in Ningxia, China. Patients will be randomly assigned to either the intervention or control group. The intervention integrates head and neck and gastrointestinal cluster symptom management, immunonutrition management, and exercise based on the Theory of Planned Behavior. The primary outcome is feasibility, assessed through acceptability, demand, fidelity, and practicality. Secondary outcomes include changes in skeletal muscle index, sarcopenia prevalence, body composition, composite biomarkers (Global Immune-Nutrition-Inflammation Index [GINI], Hemoglobin–Albumin–Lymphocyte–Platelet Score [HALP], and Prognostic Nutritional Index [PNI]), symptom burden (Head and Neck Symptom Checklist), nutritional status (Patient-Generated Subjective Global Assessment [PG-SGA]), and adherence to exercise and dietary interventions. Exploratory outcomes include behavior change mechanisms assessed using a Theory of Planned Behavior–based questionnaire.

Discussion

This pilot study is designed to evaluate the feasibility of implementing a comprehensive multimodal intervention for sarcopenia in NPC patients undergoing CCRT. The outcomes will provide preliminary evidence to guide the design of future large-scale RCTs and advance multidisciplinary care models for sarcopenia management in oncology.

Trial registration

UMIN Clinical Trials Registry, UMIN000059146.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12937-026-01296-9.

Background

Nasopharyngeal carcinoma (NPC) is a malignant tumor that originates from the epithelial cells of the nasopharynx and is the most common type of head and neck cancer [1]. Due to its asymptomatic onset and anatomically concealed location, NPC is often diagnosed at an advanced stage. The standard treatment is definitive concurrent chemoradiotherapy (CCRT) [2], which, although generally effective, can cause significant physiological complications and place a substantial psychological burden.

Among these complications, sarcopenia has emerged as a significant concern. Both the tumor itself and its aggressive treatment modalities contribute to the development of sarcopenia, a progressive skeletal muscle disorder characterized by declines in muscle strength, mass, and physical performance [3]. It is commonly categorized into three stages: pre-sarcopenia, marked by decreased muscle mass without a loss of strength; sarcopenia, involving reductions in both muscle mass and strength; and severe sarcopenia, which includes significant losses in muscle mass and strength, leading to substantial impairments in physical function [4]. A more specific condition is sarcopenic obesity, defined by the coexistence of reduced muscle mass and function and excess body fat (body fat percentage > 25% for men or > 35% for women) [5].

The prevalence of sarcopenia among NPC patients is alarmingly high, reaching up to 39.4% [6]. It serves as a key indicator of a patient’s nutritional status and immune function, reflecting their body’s ability to handle the stresses of cancer and its treatment [7]. Sarcopenia not only reduces the sensitivity and accuracy of cancer treatments but also increases the risk of adverse reactions, extends hospital stays, delays recovery, raises healthcare costs, and lowers quality of life [8, 9]. Significantly, the presence of sarcopenia can indicate an unfavorable overall nutritional and immune status in patients and elevates the risk of infection and treatment toxicity. It creates a vicious cycle: decreased nutritional status impairs immune function, which then diminishes treatment tolerance [10, 11]. Poor immune function further raises the risk of infections and treatment toxicity, often leading to therapy interruptions and severe complications [12]. These complications may contribute to higher mortality rates, reduced bone density, and an increased risk of osteoporosis and cachexia [13]. As a result, patients become more vulnerable to adverse treatment reactions, worsening malnutrition [10], infections, and even abandonment of cancer treatment [14]. Therefore, addressing sarcopenia is essential for improving treatment outcomes and reducing mortality rates in NPC patients [15].

Despite the high prevalence of sarcopenia and its substantial impact on the patient’s health and quality of life, effective management remains a significant clinical challenge. No globally recognized pharmacological treatments offer high efficacy and minimal side effects [16]. In recent years, nonpharmacological interventions have gained attention as promising supportive strategies [15, 17].

Traditional nutritional therapies have primarily focused on nutrient supplementation and the preservation of skeletal muscle mass, often neglecting essential aspects such as the monitoring and maintenance of muscle function. Sarcopenia, however, represents a complex and multifactorial syndrome involving the interplay of malnutrition, immune dysregulation, and systemic inflammation, thus offering a more comprehensive characterization of patient vulnerability. While sarcopenia has been extensively investigated in gastric [18], esophageal [19], and lung cancers [20], research dedicated to its prevention and management in NPC remains limited. To bridge this gap, the present study aims to assess the feasibility of a multimodal intervention for preventing sarcopenia in NPC patients undergoing definitive therapy.

To develop this intervention, we adopted the updated Medical Research Council (MRC) framework for complex interventions, which emphasizes a flexible, iterative, and non-linear approach, ideal for tackling multifaceted health challenges involving multiple interacting components [21]. The framework comprises four key phases: development, feasibility and piloting, evaluation, and implementation [22]. This study focuses on the feasibility phase, assessing the practicality and acceptability of a proposed multimodal intervention. The development phase was conducted by a multidisciplinary team (MDT) through an iterative process that included evidence synthesis, stakeholder engagement, economic evaluation, contextual assessment, and program theory development [23]. Drawing on insights from these phases, the MDT designed a multimodal intervention model composed of four key components: (a) symptom management targeting head and neck; (b) symptom management targeting gastrointestinal clusters; (c) immune-nutritional support, and (d) exercise interventions. The model incorporates six core strategies, is led by an MDT coordinated by a head nurse, and is implemented throughout the entire course of CCRT.

In the MRC framework, this study is situated in the feasibility phase, which assesses the practicality of an intervention. As noted in the CONSORT 2010 statement [24], pilot studies are a subset of feasibility studies, conducted on a smaller scale to inform a future definitive trial. Therefore, this study is designed as a pilot randomized controlled trial (RCT) to provide feasibility evidence and preliminary estimates for a future full-scale RCT.

Study aim

This pilot RCT aims to evaluate the feasibility, acceptability, and practicality of implementing the proposed multimodal intervention model in NPC patients undergoing CCRT, and to generate preliminary estimates to inform the design of a future full-scale RCT.

Hypothesis

We hypothesize that the proposed multimodal intervention will be feasible and acceptable in NPC patients undergoing CCRT, and may be associated with favorable trends in sarcopenia-related outcomes.

Materials and methods

Study design

The study is a two-arm, assessor-blinded, parallel-group, pilot RCT with an allocation ratio of 1:1. Participants will be randomly assigned to one of two groups: the intervention group or the usual care group. The usual care group will receive standard care and will be referred to a dietitian when clinically indicated. Participants in the intervention group will receive a multimodal intervention throughout the entire course of definitive treatment.

Study population

Patients diagnosed with NPC and scheduled to undergo definitive CCRT at General Hospital of Ningxia Medical University, China, between September 2025 and May 2026 will be invited to participate in this study. All participants will follow a standardized treatment protocol. The study has been approved by the Ethics Committee of St. Luke’s International University and the General Hospital of Ningxia Medical University. Written informed consent will be obtained from all participants and an attending family member. The trial has been registered with the University Hospital Medical Information Network (UMIN) (registration number: UMIN000059146).

Sarcopenia diagnosis criteria

Sarcopenia diagnosis adheres to the criteria recommended by the 2019 Asian Working Group for Sarcopenia (AWGS) [25]: (1) Low muscle mass, evaluated through Bioelectrical Impedance Analysis (BIA): Men: Skeletal muscle index (SMI) < 7.0 kg/ m²; Women: SMI < 5.7 kg/m². (2) Reduced muscle strength, assessed by grip strength: Men: < 28.0 kg; Women: < 18.0 kg. (3) Impaired physical performance, indicated by a 6-minute walk speed < 1 m/s. Diagnosis of sarcopenia is confirmed if an individual meets both criteria (1) and (2) or criterion (3).

Inclusion criteria

Patients will be included if they meet all of the following:

• A histologically confirmed diagnosis of nasopharyngeal cancer (NPC) and are undergoing initial concurrent chemoradiotherapy (CCRT);

• Aged between 18 and 80 years;

• An Eastern Cooperative Oncology Group (ECOG) performance status of 0–2;

• Intact limb function;

• Supported by at least one family member who can attend health education sessions and assessments with the patient;

• Clinically assessed and approved for participation by their attending physician.

Exclusion criteria

Patients will be excluded if they meet any of the following.

• Sarcopenia and/or other malignant tumors prior to treatment;

• A diagnosis of mental illness or cognitive impairment, as assessed through clinical judgment by the attending physician and review of medical records;

• The presence of an implanted pacemaker;

• Hearing or visual impairments, or aphasia;

• Physical activity restrictions due to multiple cardiovascular diseases, poorly controlled hypertension, or bronchial asthma;

• Medically prescribed dietary restrictions that conflict with the study’s nutrition plan (e.g., chronic kidney disease requiring sodium, protein, potassium, or phosphorus restrictions).

Treatment protocol

All participants will receive a standardized treatment regimen consisting of radiotherapy and chemotherapy. Radiotherapy will be delivered using three-dimensional conformal intensity-modulated radiation therapy (IMRT), administered once daily, five days per week. Prescribed doses are as follows: P-GTV (primary gross tumor volume) and PTVnd (involved lymph nodes) at 69.96 Gy (2.12 Gy × 33 fractions), PTV1 (high-risk region) at 60.06 Gy (1.82 Gy × 33), and PTV2 (low-risk region) at 50.96 Gy (1.82 Gy × 28).

Chemotherapy includes induction and concurrent phases. Patients with T3–T4 or N2–N3 disease will receive induction chemotherapy every 21 days for 3–4 cycles using either the GP regimen (gemcitabine 1.0 g/m² on Days 1 and 8, plus cisplatin 80 mg/m² on Day 1) or the TPF regimen (docetaxel 60 mg/m² and cisplatin 60 mg/m² on Day 1, plus fluorouracil 600 mg/m² on Days 1–5). Concurrent chemotherapy involves either cisplatin or nedaplatin at 100 mg/m² every 21 days for two cycles or 30 mg/m² weekly for 6–7 cycles.

Sample size

We plan to recruit 15 participants per group (total N = 30). This sample size falls within the commonly recommended range of 10 to 35 participants per arm for pilot studies [26, 27], providing a sufficient basis. This size also allows for potential attrition during follow-up while preserving the ability to explore trends and assess the acceptability of the intervention components across three domains (nutrition, physical activity, behavioral support).

Randomization and masking

Participants will be recruited through outpatient oncology clinics by the attending physicians. A research nurse, who is not involved in the intervention delivery, will screen patients for eligibility based on predefined inclusion and exclusion criteria. Eligible patients will then meet with the principal investigator (PI), who will provide detailed study information and obtain written informed consent.

An independent statistician will generate the randomization sequence using block randomization (block size = 4) via SPSS, ensuring balanced group allocation in this homogeneous cohort. Allocation concealment will be maintained through sequentially numbered, opaque, tamper-evident sealed envelopes prepared by non-study personnel. After a blinded research coordinator confirms eligibility and completes baseline assessments, the next consecutively numbered envelope will be opened by the randomization officer to assign participants (1:1) to intervention or control. Outcome assessors collecting body composition, biomarkers, and patient-reported outcomes will remain blinded to group allocation throughout the study. Data analysts will be blinded until the primary feasibility analysis is complete to mitigate detection and reporting bias.

Intervention

Intervention procedure

Participants will undergo an induction chemotherapy phase of 3–4 cycles, followed by a CCRT phase consisting of 31–33 radiotherapy sessions. The total treatment duration is approximately 120–140 days. Based on the specific clinical course of NPC, key assessment and intervention time points have been established (Fig. 1):

Fig. 1.

Key assessment and intervention time points

• T0: Baseline (pre-intervention)

• T1: 12 ± 2 days after completion of induction chemotherapy

• T2: First radiotherapy session (± 1 day)

• T3–T6: 7th, 14th, 21st, and 28th radiotherapy sessions (± 1 day)

• T7: End of CCRT

• T8: Four weeks post-intervention

To ensure fidelity in delivering the multidisciplinary intervention, two coordination and orientation sessions will be held prior to initiation, aligning all participating healthcare professionals on the implementation process. An intervention manual will be developed to standardize procedures, outlining session content, communication strategies, and safety protocols related to nutrition, physical activity, and support based on the Theory of Planned Behavior. This manual will function as both a training resource and an operational guide. Throughout the study, regular team meetings and supervision sessions will be conducted to reinforce adherence, address challenges, and maintain consistency. Each team member will be provided with a detailed implementation checklist to guide the structured delivery of the intervention.

The intervention comprises six core procedures, detailed in Table 1. Each procedure, aligns with the multimodal intervention model and is coordinated by the PI (head nurse), supported by an MDT.

Table 1.

Intervention procedure

Step	Intervention component	Intervention content
1	Assessment and planning	1. Initial meeting to introduce the intervention.
		2. Comprehensive assessment: Evaluating dietary intake, cooking skills, symptoms, nutritional status, and risk factors.
		3. Personalized multimodal intervention: Tailoring dietary and exercise plans based on patient needs.
2	One-on-one health education (4 sections) (nurses)	Structured based on the Theory of Planned Behavior to enhance patient motivation, beliefs, and adherence.
		1. General Education: Treatment plan overview, side effects, and coping strategies.
		2. Psychological Preparation: Managing anxiety and building resilience.
		3. Nutritional Education: Energy and protein requirements with personalized guidance.
		4. Exercise Education: Safe and effective training methods.
		5. Educational Materials: Providing written guides and videos.
		6. Family Involvement: Requiring included family member to participate for better compliance.
3	Weekly tracking (nurses)	1.Track progress and skill mastery.
		2. Assess nutritional status and complications.
		3. Monitor dietary intake and symptoms.
		4. Monitor adherence to nutrition and exercise plans.
		5. Provide feedback on implementation and adjustments.
		6. Conduct Q&A sessions to address patient concerns.
4	MDT joint consultation for complex cases	1. Reassessment: Dietary intake, symptoms, and challenges.
		2. Identify barriers and develop solutions.
		3. Provide additional patient guidance and support.
5	MDT key time point assessments	1.Track dietary intake and symptoms.
		2. Assess nutritional status and complications.
		3. Monitor progress and skill development.
		4. Provide feedback on implementation.
		5. Conduct Q&A sessions.
6	Case summary and reflection	1. Evaluate nutritional and immune status indicators.
		2. Assess adverse reactions and intervention appropriateness.
		3. Reflect on challenges and areas for improvement.

Core procedures

1. Initial assessment and planning: At baseline (T0), the PI will lead the MDT in conducting a comprehensive assessment of each participant. Based on the findings, an individualized intervention plan will be formulated according to the strategic framework outlined in Table 2, including personalized immunonutrition and exercise prescriptions. The PI will oversee and coordinate the implementation of this plan throughout the intervention period.

2. Personalized health education: Between T0 and T1, participants and their attending family member will engage in four individualized, face-to-face health education sessions delivered by the nursing team. These sessions will address key topics such as disease awareness, psychological readiness, side effect management, immune-nutritional strategies, and safe exercise practices. Both participants and family members will maintain a weekly 3-day food record and exercise diary to support personalized feedback and monitor adherence.

3. Ongoing weekly monitoring: Beginning with the induction chemotherapy phase, the nursing team will conduct weekly monitoring of dietary intake, body composition, symptom burden, and adherence to immunonutrition and exercise protocols. Tailored feedback and behavioral reinforcement will be provided to support sustained engagement with the intervention.

4. MDT joint consultation for complex cases: Participants exhibiting ≥2.5% weight loss or identified as being at risk for pre-sarcopenia will receive targeted MDT consultations. These sessions will involve a collaborative review of the participant’s status and the development of responsive, individualized management strategies.

5. MDT key time point assessments: Structured MDT meetings will be held at T1, T5, and T7, corresponding with critical clinical milestones. The PI will present current assessment data, highlight concerns, and facilitate team discussions to refine or adapt the intervention plan as needed for the next treatment phase.

6. Case Summary and Reflection: Following the conclusion of the intervention for each individual participant, the MDT will undertake a case-specific review. This process involves examining the implementation rationale, evaluating stakeholder acceptance and feasibility, and extracting key lessons. These cumulative insights will drive the ongoing optimization and refinement of the intervention model.

Table 2.

Intervention strategies

Immunonutrition prescription
Category	Target	Strategy
Energy Intake	30–35 kcal/kg/day	Frequent small meals (5–6/day), energy-dense foods (healthy fats like olive oil, avocado, nuts), ONS if intake is < 75% of needs.
Protein	1.5–2.0 g/kg/day	High-quality proteins (lean meat, fish, dairy, tofu), leucine-rich sources (whey protein, soy), texture modification for dysphagia.
Fat	25–35% of total daily energy intake	Prioritize monounsaturated (olive oil, nuts) and polyunsaturated fats (fatty fish, flaxseeds), limit saturated and trans fats.
Micronutrients	Vitamin D (800–2000 IU/day), Calcium (1000–1200 mg/day), B12 (2.4 mcg/day), Folate (400 mcg/day), Iron (if anemic), Zinc (10–15 mg/day), Magnesium (300–400 mg/day)	Promote intake through food sources (dairy, fish, nuts, leafy greens) and supplements if necessary.
Antioxidant	Moderate intake	Emphasize fruits, vegetables, and nuts.
Probiotics	10–20 billion CFU/day	1. Triple Bifidobacterium Live Capsule will be prescribed to participants.
		2. Encourage participants to take yogurt containing the following strains: Bifidobacterium longum; Lactobacillus lactis; Enterococcus faecium; Lactobacillus plantarum MH-301; Bifidobacterium animalis subsp. lactis LPL-RH; Lactobacillus rhamnosus LGG-18; Lactobacillus acidophilus.
Oral Nutritional Supplements (ONS)	High-protein, high-energy formulas (e.g., ≥ 1.5 kcal/mL, ≥ 20 g protein per serving)	1. Low-risk patients (mild weight loss, no dysphagia): Standard dietary counseling with optional ONS.
		2. Moderate-risk patients (5–10% weight loss, mild-moderate dysphagia): Early ONS initiation with close monitoring.
		3. High-risk patients (> 10% weight loss, severe dysphagia): Mandatory ONS; consider enteral nutrition if needed.
		4. ONS Supply Timeline: (1) Weeks 1–2: Early ONS introduction (2–3 servings/day, 600–900 kcal, 40–60 g protein). (2) Weeks 3–5 (Peak toxicity phase): Monitor mucositis, dysphagia, and taste changes; adjust consistency (semi-liquid/pudding-like). (3) Weeks 6–7: Continue ONS, add parenteral support if intake < 60% of needs.
Hydration	30–35 mL/kg/day	1. Frequent small sips, especially if mucositis is present.
		2. Avoid caffeine and alcohol to prevent dehydration.
		3.Use electrolyte-rich fluids (coconut water, oral rehydration solutions).
Exercise prescription
Category	Method	Strategy
Resistance training	1. Resistance Bands: Squats, lunges, seated rows	1.Intensity: Moderate (6–8/10 perceived exertion)
	2. Free Weights: Dumbbell presses, bicep curls	2. Frequency: 2–3 times per week
	3. Leg Press/Chest Press: Target major muscle groups	3. Duration: 30–45 min per session
		4. Progression: Gradually increase weight/resistance as tolerated.
Aerobic exercise	1. Walking (treadmill, outdoor walking, stationary cycling)	1. Intensity: Light to moderate (3–5/10 perceived exertion)
		2. Frequency: 3–5 times per week
	2. Low-impact activities (e.g., swimming, cycling)	3. Duration: 20–30 min per session
		4. Progression: Gradually increase duration/intensity as tolerated.
Balance & Flexibility training	The eight movements of BADUANJIN	1. Intensity: Low to moderate, adaptable to patient’s ability.
	1. Two Hands Hold up the Heavens – Stretch shoulders, relax upper body.
	2. Drawing the Bow to Shoot the Hawk – Stretch chest, shoulder flexibility.
	3. Separate the Heaven and Earth – Side stretches to improve torso flexibility.	2. Frequency: 3–4 times per week (can be done daily as part of relaxation).
	4. Wise Owl Gazes Backwards – Neck mobility, releasing tension.
	5. Sway the Head and Shake the Tail – Spinal mobility, relieve lower back stiffness.	3. Duration: 15–20 min per session.
	6. Lift the Heels and Stand on Tiptoe – Strengthen ankles and legs.
	7. Bend the Body to the Left and Right – Increase flexibility in the waist and legs.	4. Progression: Gradually increase the duration and fluidity of the movements as tolerated.
	8. Shake the Body and Eliminate Disease – Whole body relaxation and circulation boost.
Overall implement rule	Based on the patient’s physical function and chemotherapy timeline:
	① Preparation Phase: gradual low to moderate intensity resistance training combined with aerobic exercise.
	② Induction Chemotherapy Phase: rest.
	③ Radiotherapy Phase: low to moderate intensity resistance training.
	④ Concurrent Chemoradiotherapy Phase: rest.
	⑤ Radiotherapy and Chemotherapy Intermission Phase: Low to moderate intensity resistance training combined with aerobic exercise.
Gastrointestinal cluster management
Category	Pharmacological strategies	Nonpharmacological strategies
Nausea and vomiting	1. 5-HT3 receptor antagonists (e.g., Ondansetron).	1. Small, frequent meals.
	2. NK1 receptor antagonists (e.g., Aprepitant for highly emetogenic regimens).	2. Avoid spicy, greasy, and strong-smelling foods.
	3. Prokinetics (e.g., Metoclopramide) for delayed gastric emptying.	3. Acupressure on P6 (Neiguan) for nausea control.
	4. Cannabinoids (if appropriate) for refractory nausea.	4. Psychological support and relaxation therapy.
		5. Adequate hydration (ginger tea, electrolyte solutions).
Diarrhea	1. Loperamide for mild to moderate cases.	1. Avoid lactose, high-fiber, and high-fat foods.
	2. Octreotide for severe, refractory cases.	2. Oral rehydration therapy (ORS) to prevent dehydration.
	3. Probiotics (e.g., Bifidobacterium longum, Lactobacillus rhamnosus LGG) to restore gut microbiota.	3. Monitor stool frequency and hydration status.
		4. Maintain electrolyte balance (potassium, sodium).
Constipation	1. Osmotic laxatives (e.g., Polyethylene glycol).	1.Increase dietary fiber (fruits, vegetables, whole grains).
		2. Ensure adequate fluid intake (2 L/day).
	2. Stimulant laxatives (e.g., Bisacodyl for opioid-induced constipation).	3. Prune juice, warm liquids to stimulate bowel movement.
		4. Abdominal massage to stimulate peristalsis.
Head and neck cluster management
Category	Strategy
Dental and oral care	1. Complete dental check-ups and necessary repairs before CCRT.
	2. Strengthen oral hygiene.
Prevention and management of OM	1. Perform daily self-monitoring by patients.
	2. Perform weekly monitory by nurses.
	3. Apply mouthwash stepwise.
	4. Avoid spicy, acidic, or rough foods that may worsen irritation.
	5. Use ice chips or sugar-free gum to stimulate saliva production.
Prevention and management of RRD	1. Wear protective garments to reduce skin irritation.
	2. Use gentle skin care routines and avoid harsh soaps or scrubbing.
	3. Apply prescribed creams to soothe affected areas.
Dysphagia Management	1. Modify food texture (soft, pureed, or liquid diet).
	2. Use thickened fluids to prevent aspiration.
	3. Provide swallowing therapy and oral function exercises guided by speech therapists.

ONS Oral Nutrition Supply, 5-HT3 5-Hydroxytryptamine receptor 3, NK1 Neurokinin-1 receptor, CCRT Concurrent Chemotherapy and Radiotherapy, OM Oral Mucositis, RRD Radiation-Related Dermatitis

All MDT members are expected to contribute according to their specific professional expertise. To formalize their roles and responsibilities, each member signed an MDT Participation Agreement Form, affirming their commitment to collaborative, patient-centered care. Personalized intervention plans, including exercise prescriptions, immunonutrition strategies, and supportive care measures, are developed collaboratively by the MDT, considering each participant’s clinical status, functional capacity, treatment-related side effects, and personal preferences. This ensures that interventions are both evidence-based and tailored to individual needs.

The roles and responsibilities of each discipline are defined as follows: (a) Physicians: Lead medical assessments and sarcopenia diagnosis; prescribe clinical interventions; manage nutrition-related symptoms and comorbidities; and oversee rehabilitation strategies aimed at maintaining or improving muscle mass, strength, function, and relevant laboratory parameters. (b) Nurses: Conduct patient assessments and health education; monitor nutritional status; implement exercise and nutrition interventions; manage treatment-related complications; and coordinate and facilitate MDT meetings. (c) Nutritionists: Design and adapt individualized physical rehabilitation programs; screen for swallowing disorders; and provide evidence-based guidance on safe eating and exercise practices. (d) Physiotherapist: formulates individualized physical rehabilitation strategies and adjusts them accordingly; conducts screenings for swallowing disorders, provides evidence-based guidance on safe eating techniques. (e) Psychologist: Assess and manage anxiety and depression in patients requiring psychological support throughout the treatment process. (f) Clinical Pharmacist: Assist in managing adverse effects of chemotherapy and radiotherapy; contribute to symptom control, especially those related to nutrition and gastrointestinal tolerance.

As outlined previously, the intervention targets four core domains that address the primary contributors to sarcopenia: head and neck symptom cluster management, gastrointestinal symptom cluster management, immune-nutritional management, and exercise management. Each patient’s intervention plan is individualized based on these key components to ensure a comprehensive and personalized approach. The detailed strategies are presented in Table 2. The framework and trajectory of the multimodal intervention model are illustrated in Fig. 2.

Fig. 2.

Framework and Trajectory of the Multimodal Intervention Model. The model comprises four core components—symptom management targeting head, neck cluster, symptom management for gastrointestinal cluster, immunonutritional support, and exercise interventions. It integrates six key strategies, is led by a multidisciplinary team (MDT), coordinated by the PI and is implemented throughout the full course of CCRT. S: strategy; T0: baseline; T1: 12 ± 2 days after 3–4 cycles of induction chemotherapy; T2: first radiotherapy session (± 1 day); T3: seventh session (± 1 day); T4: fourteenth session (± 1 day); T5: twenty-first session (± 1 day); T6: twenty-eighth session (± 1 day); T7: end of CCRT; T8: four weeks post-intervention

Intervention goals

The multimodal intervention is structured to target key implementation and monitoring objectives across three core domains:

1. Nutrition and weight maintenance: This component is designed to support nutritional status and minimize the risk of clinically significant weight loss during treatment. In the early treatment phase (induction chemotherapy and Weeks 1–2 of radiotherapy), efforts will focus on preserving baseline energy and protein intake through close monitoring and early identification of malnutrition risk. In the mid-to-late phase (Weeks 3–7 of radiotherapy), nutritional support will be intensified, with target intakes of ≥ 25 kcal/kg/day and ≥ 1.0 g/kg/day of protein. Dietary plans will be personalized and adjusted weekly based on symptom burden, dietary tolerance, and weight trends.

2. Muscle mass preservation and exercise adherence: This component targets: ① Prevention of ≥ 2–3% reduction in skeletal muscle index (SMI); ② ≥70% adherence to prescribed exercise sessions; ③ Maintenance or improvement of physical function, measured via handgrip strength and the 6-minute walk test; and ④ Assurance of safety and tolerance, with no serious adverse events such as falls or musculoskeletal injuries.

3. Behavioral support: Grounded in the Theory of Planned Behavior, this component aims to enhance motivation, self-efficacy, and long-term adherence to nutritional and exercise behaviors. Strategies focus on improving attitudes, strengthening perceived social support (subjective norms), and enhancing perceived behavioral control to promote sustainable behavior change.

Discontinuation and suspension criteria

Voluntary withdrawal. Participants retain the right to withdraw from the study at any time without penalty or loss of benefits. Additionally, the PI may discontinue or suspend a participant’s involvement under the following circumstances: (a) The participant requests to discontinue part or all of the intervention or withdraws informed consent. (b) The PI determines that continued participation poses greater risk than potential benefit. (c) The participant initiates medications that may interfere with the safety or efficacy evaluation of the intervention. (d) The participant is found to have violated the inclusion or exclusion criteria.

Temporary suspension criteria. The intervention will be temporarily paused for one week if the participant experiences any of the following conditions: (a) white blood cell count < 1.0 × 10⁹/L; (b) platelet count < 30 × 10⁹/L; (c) grade ≥ 3 mucositis or radiodermatitis; (d) persistent vomiting (≥ 5 times/day) or diarrhea (≥ 6 times/day) lasting more than 24 h; (e) body temperature ≥ 38.5 °C; (f) high risk of falling due to fatigue or malnutrition, and (g) clinically significant airway edema requiring close monitoring. Resumption of the intervention will occur only after reassessment and approval by the MDT.

Permanent discontinuation criteria. The intervention will be permanently discontinued if any of the following conditions occur: (a) confirmed cerebral infarction; (b) uncontrolled severe hypertension with systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg; (c) end-stage renal failure with an estimated glomerular filtration rate < 15 mL/min/1.73 m² or requirement for dialysis; (d) life-threatening infections such as sepsis or septic shock unresponsive to treatment; (e) acute or decompensated cardiopulmonary failure, including acute heart failure or acute respiratory distress syndrome; (f) massive, uncontrollable bleeding, such as recurrent nasopharyngeal hemorrhage ≥ 200 mL, despite intervention; (g) severe psychiatric or cognitive disorders rendering the participant unable to comply with the protocol; or (h) rapid tumor progression causing structural complications, including brain herniation or spinal cord compression.

Decision making and documentation. All suspension and discontinuation decisions will be made collectively by the MDT. The PI will coordinate the clinical evaluation process, ensuring that adverse events are promptly reviewed. All decisions will be documented in detail, including justification and communication with the participant or their legal representative, in compliance with patient safety and ethical standards.

Safety monitoring

Participant safety will be closely monitored throughout the study. Adverse events (AEs) will be assessed and documented at each study visit, using the Common Terminology Criteria for Adverse Events (CTCAE), version 6.0 [28]. Follow-up evaluations will be conducted by trained nurses who will systematically screen for any AEs. In the event of participant withdrawal, all safety data collected prior to dropout will be retained for inclusion in the safety analysis.

Given the potential risks associated with exercise interventions, such as muscle strain, joint injury, or falls, particularly in a physically vulnerable population, the physical activity component will be introduced gradually and tailored to each participant’s functional capacity. Safety instructions will be clearly communicated to both participants and their family caregivers, and supervised sessions will be recommended when appropriate to ensure safe implementation.

Usual care

Participants in the control group will receive the standard care currently practiced at the study hospital. This includes routine nutritional and physical activity education provided by nurses at the time of diagnosis, along with nutritional risk screening conducted by physicians using the Nutritional Risk Screening 2002 (NRS-2002) tool. When clinically indicated, such as in cases of significant weight loss, patients will be referred to a dietitian through an internal system for a one-time assessment and individualized dietary advice. However, ongoing nutritional follow-up is not routinely provided.

Exercise guidance is limited to general recommendations during initial education and is not tailored or systematically monitored. Sarcopenia screening and structured tracking of physical activity are not standard components of usual care. Side effects are assessed and managed by physicians and nurses during regular outpatient visits, although this is not supported by a standardized symptom-monitoring protocol. To ensure equitable access to information, participants in the control group will receive the same educational materials as those provided to the intervention group at the time of recruitment.

Outcomes

Primary outcome: feasibility of the multimodal intervention

The primary objective is to evaluate the feasibility of implementing a multimodal intervention for sarcopenia prevention in clinical settings. Feasibility will be assessed across the following four areas:

Acceptability

Assessed through semi-structured interviews with patients and MDT members after the intervention, exploring experiences, perceptions of individual components (nutrition, exercise, symptom management, and psychological support), and perceived burden. Additionally, a structured Patient Satisfaction Survey will be used to assess satisfaction quantitatively.

Demand

Evaluated by recruitment and consent rates, session attendance, retention, and documented reasons for withdrawal or non-participation.

Implementation Fidelity

Measured using standardized checklists to ensure core components are delivered as intended.

Practicality and Adaptability

Assessed via resource utilization (e.g., staff time, materials), cost per participant, disruptions to workflow, and feedback from healthcare staff on barriers/facilitators and integration potential.

This trial also aims to evaluate the safety (Common Terminology Criteria for Adverse Events 6.0 and practicality (this was addressed above) of the intervention protocol, providing critical data to guide refinements ahead of a future full-scale RCT.

Secondary outcomes: preliminary effects on patient health and behavior

The following seven domains provide quantitative data for understanding the effects of the intervention model on health and behavior:

1. Evaluation of sarcopenia. The diagnosis of sarcopenia will be made by a physician based on the 2019 criteria established by the Asian Working Group for Sarcopenia (AWGS) [25] using the following three components:

   1. Evaluation of muscle mass: Muscle mass will be evaluated using the Skeletal Muscle Mass Index (SMI), calculated as the appendicular skeletal muscle mass (kg) divided by height squared (m²).
   2. Assessment of muscle strength: Muscle strength will be assessed via handgrip strength, measured in a standing position with the elbow fully extended, using an electronic hand dynamometer (EH101, CAMRY). Two measurements will be taken with the dominant hand, and the highest value will be recorded to the nearest 0.1 kg.
   3. Assessment of physical function: Physical performance will be assessed using the 6-Meter Walk Test. Participants will walk 6 meters at a normal pace, starting from a static position without acceleration or deceleration. The test will be conducted twice, and the average time will be recorded.

2. Body composition analysis. Body composition measurements were conducted using the ACCUNIQ BC560 body composition analyzer. The composition analyzer is manufactured by SELVAS, a South Korean company. Measured parameters include BMI, body fat mass, lean body mass index, body fat percentage, muscle mass, skeletal muscle index, etc. The BC560 comes with a mobile cart and a portable carrying case, making it convenient for bedside assessments and off-site consultations. All measurements were performed following the instruction manual.

3. Biomarker analysis. The following hematological parameters are measured at time points T0, T1, T2, T5 ,T7 and T8:(1) Nutritional Status Indicators: Serum Albumin (ALB), Total Protein (TP), (2) Inflammatory Status Indicators: Neutrophil Count (NEUT), Total Lymphocyte Count (TLC), Platelet to Lymphocyte Ratio (P/L), C-reactive protein (CRP); (3) Bone Marrow Function Indicators: Hemoglobin (HGB), White Blood Cell Count (WBC), Platelet Count (PLT).Prealbumin (PA) and 25-hydroxy vitamin D [25-(OH)D] levels will be checked at T0, T7and T8.

Given the pragmatic constraints of routine clinical care and the feasibility-focused nature of this pilot study, we did not prioritize direct assessment of detailed immunological markers (e.g., immunoglobulins or lymphocyte subpopulations). Instead, we selected composite immune-nutritional-inflammatory indices as robust surrogate measures. These indices incorporate routinely available laboratory parameters, enabling clinically interpretable and cost-effective assessments of immune, nutritional, and inflammatory status in patients undergoing CCRT.

Upon obtaining the relevant biomarker, the following indicator will be calculated using this formula:

(1) GINI (Global Immune-Nutrition-Inflammation Index):

(2) HALP (Hemoglobin, Albumin, Lymphocyte, Platelet Score):

(3) PNI (Prognostic Nutritional Index):

• (d)Head and Neck Symptom Checklist©. The Head and Neck Symptom Checklist© was developed by Schmidt et al., consisting of 17 symptom items, including 12 common symptoms and five systemic symptoms, with the option to add other relevant symptoms [29]. Patient symptoms are evaluated using a 5-point Likert scale. The Cronbach's α coefficient of this scale is 0.92. Content validity testing was conducted with the Patient-Generated Subjective Global Assessment (PG-SGA), yielding sensitivity rates of 79%-98%, specificity rates of 99%-100%, positive predictive values of 92%-100%, and negative predictive values of 94%-100%. In this study, radiation-induced oral mucositis was recorded under the “other” symptom category provided in the checklist, thereby maintaining the original validated structure of the instrument.
• (e)Patient-Generated Subjective Global Assessment Scale (PG-SGA). This scale was developed by Dr. Faith D. Ottery in 1996 and is specifically used for nutritional screening in cancer patients [30]. It consists of two parts: the patient self-assessment form, which includes body weight, dietary intake, symptoms, activity, and physical function; and the healthcare professional assessment form, which includes relevant diagnoses, stress status, and physical examination. The final score, obtained by combining the scores from both parts, is used to determine the overall nutritional status.
• (f)Exercise adherence score. The compliance will be calculated using the following formula:

Where: Actual Duration = Minutes of exercise completed per session. Prescribed Duration = Minutes of exercise recommended per session. Intensity Level = Measured by heart rate, perceived exertion, or METs (Metabolic Equivalent of Task).

This formula accounts for both the duration and intensity of the exercise performed relative to the prescribed values, providing a more comprehensive measure of adherence. Compliance categories are: (1) high compliance: ≥ 80% of prescribed sessions completed, (2) moderate compliance: 50–79% of prescribed sessions completed, and (3) low compliance: < 50% of prescribed sessions completed.

• (g)Dietary implementation rate. The implementation will be calculated using the following formula:

Where: Average actual protein/energy intake = Mean daily intake recorded during the intervention, based on 3-day food diaries. Prescribed protein/energy intake = Daily protein and energy targets set by the dietitian. This calculation reflects the extent to which the participant adhered to their individualized nutrition plan. Adherence levels will be categorized as follows: High adherence: ≥ 80% of prescribed intake achieved; Moderate adherence: 50–79% of prescribed intake achieved; Low adherence: < 50% of prescribed intake achieved.

Exploratory outcomes: behavioral change and theoretical mechanisms

To examine the theoretical mechanisms underpinning the intervention, a Theory of Planned Behavior-based questionnaire will be administered at baseline and post-intervention. This instrument assesses key TPB constructs of attitude, subjective norms, perceived behavioral control, and behavioral intention, specifically in relation to nutrition, exercise, and symptom management behaviors, along with self-reported adherence to intervention components. The questionnaire was developed based on Ajzen’s TPB framework and adapted from validated instruments used in prior health behavior research [31, 32], with modifications tailored to the NPC population and the intervention context.

This theory-based adaptation is consistent with accepted practices in pilot and behavioral intervention research, where it is common to tailor validated TPB items for specific populations without requiring full psychometric revalidation. The structured adaptation process, grounded in well-established TPB constructs, ensures that the tool is both theoretically sound and contextually relevant. As such, it serves as a dual-purpose instrument to evaluate behavioral engagement and explore the psychological drivers of change in this specific patient group [33, 34].

Covariate data questionnaires

1. Social demographics, lifestyle, and health behaviors survey. The self-designed questionnaire will collect the following information: (1) Demographics: Age, gender, education, income, household composition, (2) Lifestyle & Health Behaviors: Dietary habits, sleep patterns, smoking/alcohol use, healthcare utilization, and (3) Physical Activity: Exercise frequency, type, duration, and sedentary behaviors.

2. 3-day food record. To assess dietary intake, a 3-day food record will be collected, where participants will log all food and beverages consumed, including portion sizes, food types, and meal timing [35]. They will be instructed to record intake immediately after eating, estimate portions accurately, and provide detailed descriptions. The recorded data will be used to evaluate dietary patterns, assess nutritional adequacy, and guide adjustments for the next week's intervention strategy.

3. Exercise diary. To assess physical activity, participants will maintain an exercise diary, recording all daily activities related to movement and exercise. The diary will include details such as the type of activity, duration, intensity, and time of day. Participants will be instructed to log their activities immediately after completion to ensure accuracy. Examples of recorded activities may include walking, stretching, strength training, or other exercises. This data will be used to evaluate physical activity levels, monitor changes over time, and adjust intervention strategies accordingly.

4. Adult Comorbidity Evaluation-27(ACE-27). It is a tool designed to assess the comorbidity burden in adult patients, helping to quantify the severity of comorbid conditions and adjust for their impact on treatment outcomes. Developed by Piccirillo et al. [36], the ACE-27 evaluates 27 different medical conditions across various organ systems, providing a comprehensive understanding of how additional health problems might affect a patient's prognosis, treatment decisions, and overall quality of life.

Data collection

The data collection schedule is outlined in Table 3.

Table 3.

Data collection schedule

Variables	T0	T1	T2	T3	T4	T5	T6	T7	T8
Social Demographics, Lifestyle, and Health Behaviors Survey	×							×	×
Adult Comorbidity Evaluation-27 (ACE-27)	×							×	×
Body composition	×	×	×	×	×	×	×	×	×
Handgrip strength	×	×	×	×	×	×	×	×	×
6-Meter Walk Test	×	×	×	×	×	×	×	×	×
3-Day Food Record	×	×	×	×	×	×	×	×	×
Exercise Diary	×	×	×	×	×	×	×	×	×
Prealbumin (PA)	×							×	×
25-hydroxy vitamin D [25-(OH)D]	×							×	×
Serum Albumin (ALB)	×	×	×			×		×	×
Total Protein (TP)	×	×	×			×		×	×
Neutrophil Count (NEUT)	×	×	×			×		×	×
Total Lymphocyte Count (TLC)	×	×	×			×		×	×
Platelet to Lymphocyte Ratio (P/L)	×	×	×			×		×	×
C-reactive protein (CRP)	×	×	×			×		×	×
Hemoglobin (HGB)	×	×	×			×		×	×
White Blood Cell Count (WBC)	×	×	×			×		×	×
Platelet Count (PLT)	×	×	×			×		×	×
The Head and Neck Symptom Checklist©	×	×	×	×	×	×	×	×	×
The Patient-Generated Subjective Global Assessment Scale	×	×	×	×	×	×	×	×	×
The Exercise Adherence Score	×	×	×	×	×	×	×	×	×
Dietary Implementation Rate	×	×	×	×	×	×	×	×	×

T0 Baseline (prior to any intervention), T1 12 ± 2 days after completing 3–4 cycles of induction chemotherapy, T2 The first session of radiotherapy (± 1 day), T3 The seventh session of radiotherapy (± 1 day), T4 The fourteenth session (± 1 day), T5 The twenty-first session (± 1 day), T6 The twenty-eighth session (± 1 day), T7 The end of concurrent chemoradiotherapy. T8 4 Four weeks post-intervention

• T0, T7, and T8: A blinded assessment nurse (who is unaware of the group assignment) will be responsible for collecting all data at these time points.

• T1–T6: The Principal Investigator (PI) and other members of the nursing team will handle the data collection at these time points. These data serve as the basis for analysis and also provide evidence to guide the subsequent intervention strategies.

Statistical analysis

Descriptive and feasibility analysis. Descriptive statistics will summarize baseline characteristics (sociodemographic/clinical variables) and feasibility outcomes. Continuous variables will be reported as mean (SD) or median (IQR) based on normality (Shapiro-Wilk test); categorical variables as frequencies (%). Feasibility metrics (acceptability, demand, fidelity, practicality) will be presented as proportions with 95% confidence intervals (CIs) using Wilson score methods. No inferential testing (e.g., t-tests, chi-square) will be performed for baseline or feasibility comparisons, consistent with pilot trial recommendations.

Effect size estimation for secondary outcomes. For secondary efficacy outcomes (sarcopenia prevalence, body composition, biomarkers, symptom burden, nutritional status), effect sizes with 95% CIs will replace hypothesis testing and for the continuous outcomes (e.g., muscle mass, biomarkers) Hedges’*g* (bias-corrected standardized mean difference) will quantify group differences with values of 0.2, 0.5, and 0.8 representing small, medium, and large effects, respectively. For binary outcomes (e.g., sarcopenia prevalence) the relative risk (RR) with 95% CI (Koopman asymptotic score) will be reported. Longitudinal changes within groups will use Cohen’s *d* (baseline vs. T8) with 95% CI.

Exploratory and sensitivity analyses. Exploratory analyses will assess behavior change mechanisms (Theory of Planned Behavior) using Spearman’s correlations (ρ) with 95% CIs. Biomarker trajectories (e.g., GINI, HALP, PNI) will be visualized via Loess smoothing curves. Missing data will be reported as percentages; complete-case analysis will be primary, with sensitivity analysis (last observation carried forward) if more than 5% of data are missing.

Software and rationale. Analyses will use R (v4.3+; packages: effect size, epiR). This approach prioritizes estimation over testing, reporting magnitude (effect sizes) and precision (95% CIs) to inform future definitive trials. Wide CIs will highlight uncertainty due to pilot sample size (n = 30), aligning with CONSORT guidelines for feasibility studies.

Quality control

Two surveyors were designated and received standardized training prior to the official investigation. Each surveyor conducted preliminary assessments on the same patients, followed by a discussion and analysis after evaluating three patients, until their assessment results were consistent. Data entry was performed by two researchers using SPSS 29.0 and Mplus 8.3, with all information undergoing secondary verification. During the data entry process, a valid range for data values was established to ensure accuracy.

Ethical considerations

This study will be conducted in accordance with core ethical principles, including non-maleficence (do no harm), voluntary participation, confidentiality, and the protection of personal privacy and data. All participants and their accompanying family members will receive a clear explanation of the study’s purpose, methodology, potential benefits, and associated risks prior to enrollment. Written informed consent will be obtained from all participants and family members involved, who will retain the right to withdraw from the study at any time without penalty or consequence. To ensure fairness and equity, participants in the control group will be provided with the same educational materials.

Confidentiality and data management

Strict confidentiality will be maintained throughout the study. All collected data will be securely stored for five years in both a locked physical archive and an encrypted cloud system at St. Luke’s International University. After this retention period, all data will be permanently deleted or shredded. Although there are no current plans for follow-up studies, the collected data may be used in future research projects conducted solely by the principal investigator, subject to renewed approval from the Research Ethics Committee. Any research findings will be presented at national and international academic conferences and submitted to peer-reviewed journals. Importantly, no personally identifiable information will be disclosed in any publication, ensuring participants’ privacy is safeguarded to the fullest extent permitted by law.

Discussion

This protocol describes a pilot RCT primarily designed to evaluate the feasibility of implementing a multidisciplinary, multimodal intervention for the prevention and management of sarcopenia in patients with NPC undergoing CCRT. Informed by the MRC framework, the intervention combines personalized immunonutrition, structured exercise, and comprehensive management of treatment-related side effects, including head and neck and gastrointestinal symptom clusters.

Despite its significant clinical implications, sarcopenia remains under-recognized and under-assessed in routine practice for NPC patients. It adversely affects both the physiological and psychological aspects of health, and has been shown to negatively impact disease-free survival, overall survival, and quality of life [37]. Although sarcopenia was officially included in the ICD-10 classification in 2016 [38] and has garnered increasing attention from researchers and clinicians, its assessment remains non-standardized, and systemic prevention strategies are notably lacking [39]. Given its multifactorial nature and profound impact on cancer treatment outcomes, there is a critical need to develop and integrate a practical, evidence-based management model into the treatment trajectory of NPC.

Previous studies have investigated various components of interventions across different cancer types. To address the complex and multifactorial nature of sarcopenia, many have adopted multimodal intervention strategies that simultaneously target multiple contributing factors through integrated approaches. This methodology has been suggested to offer advantages over traditional single-modality interventions in certain clinical contexts [40].

For example, Charlie et al. randomized community-dwelling adults with incurable cancer to either a personalized exercise and nutrition-based program or standard care. The intervention group demonstrated high adherence, with more than 80% adherence achieved by 76% of participants, and qualitative findings indicated enhanced capability, opportunity, and motivation. Notably, the program was also associated with cost savings compared with standard care [41]. Similarly, Naito et al. implemented a combined nutritional and exercise intervention in patients with pancreatic and non-small cell lung cancers, reporting acceptable feasibility and indications of potential clinical benefit [42]. Previous studies have shown that multimodal rehabilitation interventions are safe and may help preserve weight and muscle mass across diverse cancer populations [43, 44]. Taken together, these findings highlight the potential of multimodal approaches to deliver feasible and contextually appropriate supportive care for cancer patients.

However, the evidence is not uniformly conclusive. Several studies have reported mixed or non-significant outcomes, suggesting that the effectiveness of multimodal interventions may vary based on patient population, cancer type, or intervention fidelity. For instance, Bye et al. found no significant difference in weight loss between intervention and control groups among head and neck cancer patients undergoing combined nutritional and exercise therapy [45]. Likewise, Storck et al. evaluated a leucine-enriched supplement combined with nutritional support and physical exercise in patients with advanced cancer but observed no significant improvements in physical performance, as measured by the Short Physical Performance Battery (SPPB) [46]. A 2020 meta-analysis further concluded that multimodal interventions incorporating individualized dietary counseling, oral nutritional supplements (ONS), and structured resistance training during cancer treatment did not result in significant differences in weight or muscle loss compared to standard care across 22 studies [47].

These inconsistent findings highlight the complexity of sarcopenia management and the need for a more nuanced, context-specific understanding of non-pharmacological interventions. In response, our study aims to investigate tailored intervention strategies for NPC patients undergoing CCRT, with the goal of generating clearer and more targeted evidence to inform clinical practice.

Given the complex and multifactorial nature of sarcopenia in NPC patients undergoing CCRT, the adoption of the MRC Framework was a deliberate and strategic choice for guiding intervention design [48]. Originally developed by the British MRC and later updated in collaboration with the NIH, the framework supports the development and evaluation of complex interventions involving multiple interacting components and contextual influences [49]. Its phased, iterative structure is particularly well-suited to capturing the dynamic interplay of sarcopenia-related factors such as malnutrition, inflammation, treatment toxicity, physical inactivity, and comorbidities [21].

By facilitating the integration of these interacting elements into a coherent and adaptable intervention strategy, the MRC Framework supports both scientific rigor and real-world applicability. It emphasizes key principles, including evidence synthesis, stakeholder engagement, contextual relevance, and the development of program theory, all of which are critical for designing feasible and contextually appropriate interventions within oncology care settings [50]. A detailed overview of the evidence identification and intervention development process is provided in Supplementary Material (Appendix A).

As a first step in applying the framework, evidence synthesis was conducted through a systematic review [51]. The review highlights the effectiveness of nonpharmacological interventions in improving the nutritional and immune status of NPC patients undergoing CCRT. Oral nutritional supplements (ONS) help mitigate malnutrition and oral mucositis but have limited effects on serum protein levels. In contrast, bundled nutritional interventions, incorporating nutritional assessment, dietary education and side effect management, have demonstrated greater efficacy in improving BMI and markers such as albumin and prealbumin. Probiotic and exercise interventions also show promise, particularly in enhancing immune function and reducing cancer-related fatigue, although further validation is warranted.

To complement the literature, insights from a descriptive qualitative study involving healthcare professionals revealed practical challenges in sarcopenia management, including knowledge gaps, structural limitations, and the absence of standardized protocols [52]. Importantly, these professionals expressed a willingness to improve care through multidisciplinary collaboration.

Building on this foundation, economic feasibility and contextual appropriateness were evaluated by a multidisciplinary team (MDT). Cost-effective strategies were prioritized, such as recommending probiotic-rich yogurt in place of costlier supplements, and offering vitamin D supplementation only to patients with identified deficiencies. Although comprehensive immune profiling was not feasible owing to resource constraints, we selected GINI, HALP, and PNI as accessible blood-based composite indices reflecting complementary systemic dimensions: nutritional reserve, immune competence, and inflammatory burden, that are highly relevant to cancer biology and potentially informative for physiological risk profiling in NPC [53–56]. Specifically, PNI serves as a marker of immune-nutritional reserve [57, 58]; HALP reflects integrated nutritional and hematological status [59, 60]; and GINI represents systemic inflammatory balance [61]. Because NPC treatment commonly precipitates a complex decline across these specific domains, these indices provide a practical and multidimensional approach for monitoring the systemic immune-nutritional-inflammatory axis, reflecting the body’s capacity to manage the challenges posed by cancer and its treatment. To further enhance the intervention’s contextual fit, key implementation strategies include fostering clear multidisciplinary collaboration, ensuring continuous monitoring throughout treatment, and delivering structured patient education to support adherence.

Additionally, a psycho-behavioral program theory grounded in the Theory of Planned Behavior (TPB) is proposed to address the physical and psychological challenges commonly faced by NPC patients. The program aims to strengthen self-efficacy, resilience, and treatment adherence, ultimately promoting better patient compliance and health outcomes. According to TPB, behavioral intentions are shaped by three core factors: attitudes, perceived social norms, and perceived behavioral control. Figure 3 presents the conceptual framework of the intervention, which is informed by the TPB. Guided by this framework, the intervention incorporates patient education to increase awareness and motivation, family involvement to create a supportive social environment, and behavior monitoring to strengthen self-efficacy and reinforce adherence behavior [62].

Fig. 3.

Conceptual Framework of the Study. TPB identifies three determinants of behavior: attitude, subjective norms, and perceived behavioral control. The intervention addresses these through: (1) patient education (Strategies 2 & 3), which improves knowledge, motivation, and attitudes; (2) family involvement (Strategies 2 & 3), which reinforces normative beliefs and supports subjective norms; and (3) behavior monitoring and guidance (Strategies 3 & 5), which enhance control beliefs, self-efficacy, and adherence. Strategy 2 = one-on-one health education; Strategy 3 = weekly tracking; Strategy 5 = multidisciplinary team (MDT) key time point assessments

Guided by this framework, our intervention employs a multidisciplinary, multimodal strategy targeting four critical domains: management of head and neck symptom clusters, gastrointestinal symptom clusters, immune-nutrition, and exercise. These components are designed to address the underlying pathophysiological mechanisms of sarcopenia, aiming to preserve skeletal muscle mass and function while enhancing treatment tolerance and clinical outcomes.

The MRC Framework enabled us to develop a comprehensive and scalable intervention by integrating a biologically targeted, multimodal therapeutic approach with a behaviorally informed implementation model. This dual structure ensures that both physiological and psychosocial aspects of sarcopenia [63] prevention are addressed. Consequently, the framework not only reinforces the scientific validity of our pilot RCT but also provides a practical blueprint for future large-scale implementation and real-world clinical integration [49].

Building on this foundation, the present pilot study aims to evaluate the feasibility, acceptability, and practicality of implementing a multimodal intervention for sarcopenia management in NPC patients undergoing CCRT. Particular attention will be given to recruitment and retention, intervention adherence, and operational challenges in delivering immune-nutrition, exercise, and symptom management components in routine clinical settings.

In addition, exploratory data will be collected to characterize preliminary trends in sarcopenia-related outcomes, including muscle mass, physical function, and immune-nutritional status. Although the study is not powered to assess efficacy, these data are expected to support refinement of intervention components, optimize outcome selection, and strengthen implementation strategies for future large-scale randomized trials.

Beyond feasibility assessment, this protocol may contribute to the methodological and theoretical understanding of complex interventions in oncology by demonstrating how biological, behavioral, and psychosocial components can be integrated within a structured framework. The insights generated may help refine future intervention models and support the translation of multidisciplinary strategies into routine cancer care.

If the intervention proves feasible, this study could inform the design of larger randomized trials to evaluate its effectiveness. It may also offer practical guidance on real-world implementation, including logistical considerations, resource planning, and healthcare provider training. In this context, the proposed multimodal approach may serve as a scalable framework for early and proactive sarcopenia management in oncology, with potential implications for patient care by addressing both physiological and psychosocial dimensions. Furthermore, identifying barriers to engagement and adherence may help refine future iterations to enhance feasibility and broader implementation.

Limitations

Several limitations should be acknowledged. As a single-site pilot study with a small sample size, the findings will primarily inform feasibility rather than efficacy and may have limited generalizability. Recruitment and retention may be challenged by the physical and psychological burden of intensive CCRT, and adherence to a multifaceted intervention may vary across participants. Resource constraints limit direct measurement of immune biomarkers, necessitating the use of composite indices, which may not fully capture underlying immunological changes. Despite these limitations, this pilot study is expected to provide important feasibility data and practical insights to guide the design of future definitive trials and the development of contextually appropriate, multidisciplinary approaches to sarcopenia management in oncology.

Abbreviations

NPC

Nasopharyngeal carcinoma

CCRT

Concurrent chemoradiotherapy

MRC

Medical research council

PG-SGA

Patient-generated subjective global assessment scale

UMIN

University hospital medical information network

SMI

Skeletal muscle index

GP

Gemcitabine + cisplatin regimen

TPF

Docetaxel + cisplatin + 5-fluorouracil regimen

MDT

Multidisciplinary team

TPB

Theory of planned behavior

GINI

Global immune-nutrition-inflammation index

HALP

Hemoglobin–albumin–lymphocyte–platelet score

PNI

Prognostic nutritional index

Authors’ contributions

LJX contributed to the funding application, the study design, wrote the main grant application and the manuscript text, and prepared the final submission; NH contributed to the conceptualization and edited the manuscript; ZFM, SL, and JM are study nurses, edited the manuscript, and will perform patient education and data collection; ZHY is the study clinician, edited the manuscript, and will be involved in patient care; WHW is the study dietitian, edited the manuscript, and will be involved in patient care; QL is the study physiotherapist, edited the manuscript, and will be involved in patient care; YB and YKX prepared the figures and will perform data curation. All authors reviewed and approved of the final manuscript.

Funding

This research was funded by the Ningxia Natural Science Foundation, China, grant number 2024AAC03617, and the APC was funded by the Ningxia Natural Science Foundation. The funders had no role in the design of this study, the collection, analysis, or interpretation of data, the writing of the manuscript, or the decision to publish the results.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of St. Luke’s International University, Japan (Approval No. 25-A031), and the Ethics Committee of the General Hospital of Ningxia Medical University, China (Approval No. KYLL-2025-1851). Written informed consent will be obtained from all participants.

Competing interests

The authors declare no competing interests.