Objectives

The primary objective of the PreHead study (Prehabilitation in Head and neck cancer patients) is to investigate the effect of nutritional prehabilitation on adverse events (complication rates and (chemo)radiotherapy toxicity) in patients with locoregionally advanced HNC and with a low or medium risk of malnutrition.

Secondary objectives are to investigate the effect of nutritional prehabilitation on nutritional status, patient-reported quality of life, recurrence and (disease-specific and overall) survival and to evaluate the cost-effectiveness of nutritional prehabilitation compared with standard care.

Study design and setting

A single-center, non-blinded, randomized controlled trial will be performed within the Department of Otorhinolaryngology – Head and Neck Surgery, Department of Oral and Maxillofacial Surgery – Head and Neck Surgery and the Department of Radiotherapy at the University Medical Center Groningen (UMCG). The UMCG is a tertiary referral head and neck oncology center in the Netherlands.

The Dutch HNC patient organization (Patiëntenvereniging Hoofd-Hals, PVHH) reviewed the complete study protocol including the patient information folder and has delivered input and feedback on the recruitment process, the secondary outcome measure ‘patient-reported outcome measures’, and ways of communicating study results to participants.

This protocol adhered to the SPIRIT 2025 guidelines [15].

Eligibility criteria

Subjects will be drawn from our population of patients with HNC, using the in- and exclusion criteria mentioned below.

Inclusion criteria

To be eligible to participate in this study, a subject must meet all of the following criteria:

1. - Primary mucosal squamous cell carcinoma;
2. - Located in the oral cavity, oropharynx, hypopharynx or larynx;
3. - Locoregionally advanced disease defined as stage III or IV according to the 8^th edition of the TNM Classification of Malignant Tumors [16]. For oropharyngeal cancer, HPV-negative TNM staging is used at the time of inclusion, regardless of the HPV status;
4. - Treated with curative intent;
5. - Low or medium risk of malnutrition based on the MUST;
6. - Pre-treatment CT scan performed up to 30 days before treatment;
7. - Age ≥18 years;
8. - Signed written informed consent.

Exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this study:

1. - Previous surgical or radiotherapeutic treatment of the neck;
2. - Multiple simultaneous primary malignancies;
3. - Disability that could interfere with questionnaire fulfillment (e.g., not speaking Dutch).

Sample size

A power analysis was performed to calculate the sample size needed. Intervention studies evaluating the effect of nutritional prehabilitation in patients with HNC have not been performed previously. Therefore, the numbers used for the power analysis are based on studies on the association between malnutrition and adverse events in patients with HNC. The rate of adverse events in the intervention arm is expected to be 15% based on the rates of adverse events in well-nourished study populations [8,17]. The rate of adverse events in the control arm is expected to be 40% based on reported rates of adverse events in malnourished patients [8] and reported odds ratios in studies on the association between sarcopenia, which is strongly associated with malnutrition, and adverse events [17,18]. To detect a clinically relevant difference of 25% between the intervention and control arm, with a two-sided alpha of 0.05 and a power of 80%, a minimum of 61 patients per arm are needed. With an expected drop-out of 5%, we will include a total of 128 patients. This analysis was performed using G*Power version 3.1.

Randomization, blinding and treatment allocation

Included patients will be randomly assigned to one of two groups: nutritional prehabilitation or standard care. Randomization will be performed using the web-based randomization module provided by REDCap. Block randomization with a 1:1 allocation ratio will be applied. Patients will be stratified based on stage (III or IV) and tumor subsite (oral cavity, oropharynx, hypopharynx and larynx). The randomization chart, including block size, is established by an independent data manager before the start of the study. Consequently, treatment allocation sequence is concealed for patients, care providers and researchers (including outcome assessors). The outcome assessors in this study are patients (self-assessment using questionnaires) and care providers (Clavien-Dindo classification, Common Terminology Criteria for Adverse Events (CTCAE), recurrence and survival).

Recruitment

Potentially eligible patients will be informed about the study by their treating physician, after which they will receive the patient information folder. Patients will be given one week to consider their decision. Signed written informed consent will be obtained prior to study participation.

Study timeline

Participant recruitment commenced on May 15, 2025 and is expected to continue until May 2028. Data collection is expected to be completed by October 2030. The first study results are anticipated by the end of 2028.

Intervention

According to current Dutch guidelines, dietary therapy, including counselling by a dietitian, is initiated in patients with a high risk of malnutrition, whereas patients with a low or medium risk do not routinely receive dietary therapy [10]. In this study, all patients with HNC are screened using the MUST at baseline. Patients with a high risk of malnutrition are treated by a dietitian as part of our current standard practice. Patients with a low or medium risk of malnutrition who meet the remaining eligibility criteria are eligible for inclusion. The nutritional prehabilitation intervention for this study is similar to the standard daily clinical care for patients with a high risk of malnutrition. Patients with a low or medium risk of malnutrition will be randomized to either the control or intervention group upon enrollment.

Nutritional prehabilitation includes nutrition counselling and education by a dietitian, oral nutritional supplements, and enteral and/or parenteral nutrition support, as appropriate for each individual patient and in accordance with the guidelines proposed by the World Health Organization (WHO), European Society for Clinical Nutrition and Metabolism (ESPEN), and the National Institute for Health and Care Excellence [11,19,20].

We aim for an energy intake of the resting energy expenditure (REE) plus 30–50% for physical activity level, illness and thermic effect of food. The equation of the Food and Agriculture Organization, WHO and United Nations University will be used to calculate the REE [19]. We aim for a protein intake of 1.2 to 1.5 g/kg/day in patients with a BMI of 20–25 kg/m². For a BMI of less than 20 kg/m², the protein requirement will be corrected to a BMI of 20 kg/m² [21]. For a BMI of more than 25.0 kg/m², Gallagher’s formula will be used to calculate protein requirement, according to local guidelines [22]. Vitamins, minerals and trace elements will be supplied in amounts equal to the recommended daily allowance and we will not be using high-dose micronutrients in the absence of specific deficiencies [20].

All patients randomized to the intervention group will receive dietary advice by a dietitian. Patients who are able to use oral intake are counseled to use an energy and protein enriched diet and will be offered oral nutritional supplements when necessary to meet estimated nutritional requirements. If oral intake is not possible or remains insufficient despite nutritional interventions (i.e., counselling and oral nutritional supplements), enteral nutritional support will be advised to the patient. Insufficient intake is defined as less than 50% of the requirement for more than one week or only 50–75% of the requirement for more than two weeks, and these are thus the indications for enteral nutritional support [20]. If enteral nutritional support is not sufficient or not feasible, we will advise parenteral nutrition support. Patients rarely need (par)enteral nutritional support in this prehabilitation stage.

The risk of developing refeeding problems will be established using the NICE guideline on nutrition support for adults [11]. In patients with a high risk of developing refeeding syndrome, nutrition support will be started at a maximum of 10 kcal/kg/day, increasing levels with 5 kcal/kg/day to meet or exceed full needs by four to seven days [11]. Vitamin B1 will be supplied in daily doses of at least 100 mg for at least five days as well as a balanced multivitamin and trace element supplement once daily for at least five days [23]. Potassium, phosphate and magnesium will be monitored and substituted, if necessary, by oral, enteral or parenteral route [11].

Dietetic consultations will be scheduled biweekly. Depending on the patients’ needs and preferences, the frequency of consultations may be increased, e.g., in case of weight loss or inability to use oral intake. These consultations may take place in-person at the outpatient department or through video or telephone calls. The first consultation takes on average 30 minutes, follow-up consultations on average 15 minutes. We expect that in 10–20% of included patients, dietary advice in the form of an energy and protein enriched diet will be sufficient and 80–90% of patients will be offered oral nutritional supplements to meet estimated nutritional requirements.

Nutritional prehabilitation will start as soon as patients are included in the study, which is within one and a half week after their first visit to the outpatient department, depending on the time needed to consider participation in the trial. The expected variation in duration of the intervention is on average three to four-and-a-half weeks. The prehabilitation intervention ends as soon as treatment for their HNC commences. Patients will still receive nutritional care as part of standard care when indicated (i.e., postoperatively and/or during (chemo)radiotherapy). Nutritional care given during treatment is the same as nutritional care that is outlined in this paragraph (i.e., given as a prehabilitation intervention). Patients undergoing (chemo)radiotherapy are all counseled by a dietitian during their treatment. Patients undergoing surgery will receive nutritional care if they are at a high risk of malnutrition (MUST score ≥2) or according to the guideline ‘perioperative nutritional management’ (i.e., inability to start oral intake within 48 hours after surgery or no more than 50% of the recommended daily energy intake on the fifth day postoperatively) [24].

Patients enrolled in the control arm of the study will receive standard care, which means they will not receive any nutritional counselling or nutritional intervention before treatment commences. They will receive nutritional counselling or intervention during (chemo)radiotherapy and postoperatively when indicated.

Study parameters/endpoints

Participant timeline

Fig 1 gives a summary of participant enrollment, interventions, and assessments (SPIRIT schedule).

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Fig 1. Participant timeline: SPIRIT schedule of enrollment, interventions, and assessments. ^aFrailty assessment includes TUG, 6-CIT, delirium risk, PHQ-2, recent falls, iADL, MUST, Katz-ADL-6. ^bNutritional assessments include handgrip strength (only at t⁰), dietary intake using 24-hour recall or food diary, BIA, PG-SGA SF and GLIM-criteria. ^cEconomic evaluation questionnaires include EQ-5D-5L, iMCQ and iPCQ. ^dQuality of life questionnaires include EAT-10, EORTC C30 and EORTC H&N35.

https://doi.org/10.1371/journal.pone.0346273.g001

Harms and safety considerations

We expect that nutritional prehabilitation will lead to fewer (serious) complications and treatment-related side effects compared with no nutritional prehabilitation. We expect a higher quality of life, equal chance of recurrence, and better survival. There is extensive experience with the dietary measures. They are based on local, national and worldwide protocols and guidelines on nutritional support for patients with (head and neck) cancer [10,11,19,20]. All patients with a high risk of malnutrition based on the MUST receive dietary measures. Patients with high risk of malnutrition are more often frail [44], and more frequently experience swallowing problems than the study population, i.e., patients with a low or medium risk of malnutrition. The study population is a low risk patient group compared with the patient group already receiving the intervention. Oral nutritional supplements and enteral nutritional support used in this study comply with the FDA regulations regarding ingredients, labeling and manufacturing process.

Given the extensive experience with the intervention in a patient population at higher risk than the study population, and the small chance of adverse events that may cause slight damage at most, this study is considered a negligible risk study.

Data collection and management

All data will be handled confidentially, and a patient identification code list will be used to link the data to the subject. All data will be collected in REDCap, a secured web application for managing online surveys and databases. Questionnaires will be sent through REDCap. In case patients prefer paper questionnaires, the questionnaire answers will be added to REDCap manually by one of the researchers.

The handling of personal data will comply with the EU General Data Protection Regulation and the Dutch Act on Implementation of the General Data Protection Regulation. Paper data will be stored for 15 years in a locked office at the UMCG, and digital data on a research drive especially made for research data storage.

Statistical methods

Baseline characteristics, primary outcomes and secondary outcomes are quantitative and will be presented categorical and continuous. Categorical variables will be presented as absolute numbers and percentages of the total. Continuous variables will be tested for normality using the Kolmogorov-Smirnov test. Continuous variables will be presented as means and standard deviations for normally distributed data, and medians and interquartile ranges for data that is not normally distributed. Between-group mean (or median) differences, rate differences and rate ratios with 95% confidence intervals (or ranges) will be calculated.

Missing values will be handled using multiple imputation, assuming that there is only missingness at random, and all analyses will be performed on an intention-to-treat and per protocol basis.

Intercurrent events may affect the estimated treatment effect. An expected intercurrent event is non-adherence to the study intervention or the use of certain foods or medications outside the advice given by the dietitians. In the case of non-adherence to the study intervention or the use of certain foods or medications, a ‘treatment policy’ strategy will be used in which we accept that this intercurrent event is part of the intervention and we expect that non-adherence to the intervention also occurs in daily practice. Loss of follow-up because participants decide to stop the study is in our opinion not an intercurrent event but a ‘missing data’ problem. Patients who discontinue or deviate from the intervention protocol will be asked to complete follow up nonetheless.

SPSS version 28.0 (SPSS Inc., Chicago, IL, USA) will be used for all statistical analyses.

For analysis of between-group differences in the primary outcome, a logistic regression analysis will be performed. The endpoints complications and toxicity will be dichotomized. In case of unbalance between the intervention and the control group, adjusted logistic regression analyses will be performed. A p-value < 0.05 will be considered as statistically significant.

Subgroup analyses will be performed using the following variables:

1. - (Intended) type of treatment (surgery versus (chemo)therapy);
2. - Subsite (larynx versus hypopharynx versus oropharynx versus oral cavity);
3. - The presence of radiological sarcopenia or not (defined with the SMI in cm²/m²);
4. - PG-SGA SF;
5. - Duration of nutritional prehabilitation intervention;
6. - Number of dietetic consultations;
7. - Dietary intake using 24-hour recall.

These variables will be added to the regression analyses.

For further analyses of between-group differences within the secondary outcomes, logistic regression analyses will be performed for categorical outcomes, cox proportional hazard regression for time-dependent outcomes (i.e., recurrence and survival) and linear regression analyses for continuous variables. A p-value < 0.05 will be considered as statistically significant.

Furthermore, an economic evaluation will be performed to compare the incremental cost-effectiveness of nutritional prehabilitation as compared with standard care. A cost-utility analysis (CUA) and cost-effectiveness analysis (CEA) will be conducted from a societal perspective. The CUA will be performed based on EQ-5D-5L defined utilities over a time horizon of one year. The CEA will incorporate the highest measured grade of complications (Clavien-Dindo classification) at 30 days postoperatively or (chemo)radiotherapy toxicities (CTCAE) at 6 and 12 weeks after the start of (chemo)radiotherapy. Health care consumption will be measured on a patient level and registered on a case-report form and partly on questionnaires (iMCQ items). Productivity losses will be measured using the iPCQ. Costs will be calculated according to the Dutch guidelines for costing research in health economic evaluations, issued by the National Healthcare Institute [45]. There will be no discounting since the time horizon of the analyses does not exceed one year. Cost-effectiveness planes and acceptability curves will be plotted, and 95% confidence intervals will be based on bootstrapping.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness

Patients will be asked to undergo several measurements that are not part of our current standard practice. These measurements entail one handgrip strength measurement, three BIA-measurements and the following questionnaires: EAT-10, iMCQ and iPCQ at respectively six, four and four time points. Furthermore, the intervention itself will require up to three sessions with a dietitian, either during a regular visit at the outpatient department or through a telephone/video call. The time burden of these extra measurements and the intervention is 185 minutes on average.

There are negligible risks associated with the investigational treatment.

Interim analysis

Not applicable.

Ethics

The study will be conducted according to the principles of the Declaration of Helsinki (amended at the 64th WMA General Assembly, Fortaleza, Brazil, October 2013) and in accordance with the principles of ‘Good Clinical Practice’ and the Medical Research Involving Human Subjects Act (WMO). This study is approved by the Medical Ethical Committee (METc) of the UMCG and is registered in the Dutch Trial Register (CCMO registry NL87676.042.24, https://onderzoekmetmensen.nl/nl/trial/57366).

Protocol amendments will only be made after a favorable opinion by the accredited METc. In case the study is ended prematurely, the sponsor will notify the METc.

Dissemination policy

Manuscripts will be submitted to open-access, peer-reviewed journals, regardless of the results. There will be no restrictions towards publication. The results of this study will also be shared with patients and participants. At the termination of the study, PVHH will deliver input on ways of communicating study results to participants. A summary of the study findings rewritten into lay language will be distributed through the patient organization in their magazine and electronic newsletter.