A comparison of the MNA-SF, MUST, and NRS-2002 nutritional tools in predicting treatment incompletion of concurrent chemoradiotherapy in patients with head and neck cancer

Concurrent chemoradiotherapy (CCRT) treatment incompletion is a known negative prognosticator for patients with head and neck cancer (HNC). Malnutrition is a common phenomenon which leads to treatment interruption in patients with HNC. We aimed to compare the performance of three nutritional tools in predicting treatment incompletion in patients with HNC undergoing definitive CCRT. Three nutritional assessment tools, Mini Nutritional Assessment-Short Form (MNA-SF), Malnutritional Universal Screening Tool (MUST), and Nutritional Risk Screening 2002 (NRS-2002), were prospectively assessed prior to CCRT for HNC patients. Patients were stratified into either normal nutrition or malnourished groups using different nutrition tools. Treatment incompletion and treatment-related toxicities associated with CCRT were recorded. A total of 461 patients were included in the study; malnourished rates ranged from 31.0 to 51.0%. The CCRT incompletion rates were 4.9–6.3% and 14.5–18.2% for normal nutrition patients and malnourished patients, respectively. The tools had significant correlations with each other (Pearson correlation 0.801–0.837, p<0.001 for all) and accurately predicted the incompletion of CCRT. MNA-SF had the highest performance in predicting treatment-related toxicity, including emergency room visits, need for hospitalization, any grade III or higher hematological adverse events, and critical body weight loss, compared to the other tools. MNA-SF, MUST, and NRS2002 were all shown to be competent tools for prediction of treatment incompletion and treatment-related toxicity in HNC patients undergoing CCRT. We suggest implementing nutritional assessment prior to treatment to improve the rate of treatment completion and to reduce treatment-related toxicity in HNC patients.


Introduction
Primary head and neck cancer (HNC), accounting for 4% of all cancers, is a disease with more than 650,000 new cases diagnosed and account for 330,000 deaths annually worldwide [1]. Taiwan is an endemic area of HNC, with one of the highest global incidence rates of 8% [2]. Risk factors for head and neck cancer often involve chronic substance abuse, particularly among lower socioeconomic classes [3][4][5]. Inevitably, patients with HNC tend to have poor self-care and nutritional deterioration [4,5]. While the standardized treatment for localized advanced HNC is concurrent chemoradiotherapy (CCRT), the intervention is commonly associated with acute toxicities such as fatigue, nausea, mucositis, xerostomia, dysphagia, and odynophagia, which may worsen malnutrition status [6].
CCRT treatment incompletion is a well-known negative prognosticator as the premature termination of treatment decreases loco-regional control, increases the risk of distant metastases, and ultimately compromises overall survival [4,[6][7][8].
Common reasons for treatment incompletion include treatment-related side effects, limited financial resources, and poor family support [8,9]. While the reasons for CCRT treatment incompletion are multifactorial, the reversible causes of treatment incompletion should be further investigated.
Malnutrition is a reversible cause of treatment incompletion of CCRT in patients with HNC [10]. Malnutrition is highly prevalent among HNC patients, with approximately 35-60% of patients reported to be malnourished at diagnosis [10][11][12]. Previous studies have reported that malnutrition is associated with increased treatment-related toxicity and treatment intolerance of CCRT in patients with HNC. Inversely, nutritional intervention has been shown to positively influence CCRT outcomes, with decreased treatment-related toxicity and treatment interruption [13]. However, few studies have used existing nutritional tools to identify malnourished patients and determine their relationship with treatment incompletion in HNC patients. Thus, to target malnourished patients for improvement of treatment completion, a study to examine the applicable nutritional tools is warranted. This prospective study aimed to (1) determine the prevalence of malnutrition among newly diagnosed HNC patients, (2) assess the correlation among different nutritional tools, and (3) test their accuracy in predicting treatment completion in HNC patients undergoing definitive CCRT.

Patient selection
This multi-center prospective study consecutively recruited HNC patients between August 2016 and December 2017 in Taiwan. Eligibility criteria included patients aged 20 years or older with histologically proven stage II-IVa primary HNC (origin of nasopharynx, oropharynx, hypopharynx, or oral cavity) and patients must have been eligible for definitive CCRT as the antitumor treatment. Patients with the following characteristics were excluded: distant metastatic disease that was unfit for the treatment with definitive CCRT, patients who were unable to provide informed consent for any reason, patients who received other treatments (e.g., surgery or induction chemotherapy) before definitive CCRT, and patients who received bio-radiotherapy (cetuximab) alone. Tumor staging was performed according to the 7th edition American Joint Committee on Cancer (AJCC) staging system. All patients provided written informed consent prior to their inclusion in the study. The study protocol was approved by the Institutional Review Board (No. 1608080002) and was conducted in compliance with the Declaration of Helsinki (1996).

Definitive concurrent chemoradiotherapy
All eligible patients received intensity-modulated or arc technique radiotherapy at a conventional fractionated daily dose of 200 cGy for 5 consecutive days per week, with a total prescribed radiotherapy dose of 7000-7400 cGy over 7 weeks. The chemotherapy regimens, including cisplatin (40 mg/m 2 every week or 100 mg/m 2 every 3 weeks), PF regimen (cisplatin 60 mg/m 2 on day 1 plus continuous infusion of 5-fluorouracil 800 mg/m 2 on days 1-5, every 2 weeks) [14], and PUL regimen (cisplatin 50 mg/m 2 on day 1, tegafur-uracil [TTY Biopharm Co. Ltd, Taipei, Taiwan] 300 mg/m 2 /day, and oral leucovorin 60 mg/day on days 1-14, every 2 weeks) [15], were administered concurrently with radiotherapy according to the treatment guidelines at our institution.
All adverse events, including emergency room visits, need for hospitalization, grade III or higher hematological/nonhematological side effects, and critical body weight loss (defined as ≥5% body weight from the pretreatment baseline) due to any reason during the CCRT period, were recorded. CCRTrelated toxicity was graded according to the Common Toxicity Criteria (CTC) of the National Cancer Institute (NCI), version 3.
Patients who received less than 90% of the protocol specified radiotherapy dose or a cumulative cisplatin dose of less than 200 mg/m 2 due to any cause were considered to have incomplete radiotherapy [16] or chemotherapy [17] treatment, respectively. Incomplete CCRT was defined as either incomplete radiotherapy or incomplete chemotherapy. Reasons for treatment incompletion were documented and included intolerance to side effects, concomitant medical illness, progressive disease, and a patients' will against medical advice.

Nutrition assessment
Three nutritional tools, Mini Nutritional Assessment-Short Form (MNA-SF), Malnutritional Universal Screening Tool (MUST), and Nutritional Risk Screening 2002 (NRS-2002), were synchronously performed within seven days of CCRT initiation. All objective and subjective variables required for nutritional assessment were obtained from the patients.

Mini Nutritional Assessment-Short Form
The MNA-SF tool consists of the following parameters: food intake, weight loss, mobility, psychological stress, neuropsychological problems, and body mass index (BMI). All parameters are scored from 0 to 2 or 3 with a total score of 0-14 [18]. Patients with a total score <12 were classified as malnourished while a total score ≥12 was classified as normal nutrition in this study.

Malnutrition Universal Screening Tool
The MUST score is calculated based on the patient's BMI, unplanned weight loss, and acute disease effect [19]. As a score is assigned from each category, the MUST score is the sum of the categorical scores, where a score ≥2 is deemed as high risk of malnutrition and patients with such scores were assigned to the malnourished group, and patients with a score <2 were assigned to the normal nutrition group in our study.

Nutritional Risk Screening 2002
The NRS-2002 system is a two-step screening procedure with an initial evaluation of BMI, weight loss, appetite, and severe disease [20]. If further evaluation is indicated, the patient is further scored by two components: nutrition and severity of illnesses. The score is age-adjusted and ranges from 0 to 7. Patients with a value ≥3 were assigned to the malnourished group and a value <3 indicated the normal nutrition group in our study.

Statistical analysis
Basic demographic data are summarized as n (%) for categorical variables and median with range for continuous variables. All eligible patients were categorized into normal nutrition and malnourished groups according to the definition of each nutritional tool. Univariate logistic regression analyses were used for in-group comparisons of treatment incompletion and treatment-related toxicity. SPSS software (version 17.0; SPSS Inc., Chicago, IL, USA) was used for statistical analysis. All statistical assessments were two-sided, and a p-value <0.05 was considered statistically significant.

Results
A total of 461 patients were recruited in this study, with a median age of 54 years (range, 24-86 years) and 402 (87%) were male (Table 1). Tumors from the oropharynx were the most common (32.8%), followed by the nasopharynx (24.9%), and hypopharynx (24.9%). In terms of staging, 305 (66.2%) patients had stage IV disease, 78 (16.9%) of patients had stage III disease, and the remaining 78 (16.9%) of patients had stage II disease.
Using the nutritional screening tools, malnutrition was recognized in 47.3%, 51.0%, and 31.0% of the cohort using the MNA-SF, MUST, and NRS-2002, respectively (Fig. 1). The Pearson correlation coefficients ranged from 0.801 to 0.837 for the tool-to-tool comparison (p<0.001 for all), indicating strong positive correlations among the three tools ( Table 2). Figure 2 shows the percentage of treatment incompletion between normal nutrition and malnourished patients according to the different tools. The completion rate of CCRT among patients with normal nutrition was 4.9%, 5.3%, and 6.3% as identified by the MNA-SF, MUST, and NRS-2002 tools, respectively, while the incompletion rate among the malnourished group ranged from 14.5 to 18.2%. Different reasons for CCRT treatment incompletion were documented (Fig. 3). All tools analyzed showed that patients with normal nutrition had a significantly lower incidence of CCRT incompletion than the malnourished cohort. Table 3 shows the ability of the nutritional tools to predict treatment-related toxicities of CCRT. All three nutritional tools performed well in predicting the need for hospitalization, any grade III or higher grade of hematologic adverse events, and critical body weight loss among HNC patients undergoing CCRT. MNA-SF performed better in identifying the risk of emergency room visits than the other two tools, while all three nutritional tools failed to recognize the risk of any grade III or higher nonhematological adverse events in HNC patients undergoing CCRT.
Among the 46 patients with incomplete CCRT, 22 (47.8%) patients were intolerant to treatment-related adverse events, 10 (21.7%) patients had medical advice, 8 (17.4%) had severe concomitant medical illness, and 6 (13.0%) had progressive disease. The reasons for CCRT incompletion stratified by different nutritional tools are shown in Fig. 4. Malnourished patients had a higher incidence rate of CCRT incompletion than patients with normal nutrition for all causes. The absolute in-group difference in the percentage of CCRT incompletion was 4.1-7.0%, 0.8-1.2%, 2.6-2.8%, and 1.2-1.7% due to treatment-related adverse events, medical advice, concomitant medical illness, and progressive disease, respectively, among different nutritional tools.

Discussion
The reversible causes of early termination of CCRT are important issues since incompletion of treatment is a well-recognized prognostic factor for HNC patients [21].
While the reasons for premature termination of CCRT are often multifactorial [21], limited literature is available on identifiable possible causes. Malnutrition is frequently associated with poor survival outcomes, poor quality of life, and higher treatment-related toxicities in patients with HNC [22]. Consequently, this study focused on the effect of malnutrition on CCRT completion in patients with HNC. We reported malnutrition as a frequent phenomenon, with a prevalence rate ranging from 31 to 51% by three different nutritional assessment tools, among HNC patients prior to CCRT. The normal nutrition group had a CCRT incompletion rate of 4.9~6.3%, compared to the malnourished group (15.6~18.2%). Malnourished patients were more susceptible to early treatment termination as  A previous study reported that the side effects of CCRT or radiotherapy are the main reasons for treatment incompletion [23,24]. In an attempt to identify patients who are more susceptible to adverse events, this study identified that malnourished patients were significantly associated with higher rates of hospitalization, grade III or higher hematological adverse events, and critical body weight loss, compared to those with normal nutrition. Although these treatment-related toxicities are not lethal, they inevitably exacerbate the malnourished patient's physical and psychological functioning; thus, patients are more likely to withdraw from treatment [24]. While previous studies have demonstrated side effects as a common reason for premature treatment termination, our study determined an association between malnutrition and side effects, which eventually led to incomplete treatment.
Our data revealed that while the three nutritional assessment tools, MNA-SF, NRS-2002, and MUST, utilize different parameters for evaluation, a significant correlation is apparent. The correlation among these three tools and their individual prognostic significance suggest that the importance of nutritional screening for malnourished patients is universal. As the most important goal is malnutrition recognition, this result shows that clinicians may use the tools for their convenience in identifying malnutrition. The apparent strength of these tools is their ease of application. While no blood test or image interpretation is needed, tools can be easily applied by all medical staff on the cancer team. As the importance of malnutrition in these patients is recognized, an organized protocol to provide nutritional intervention is essential. The easy accessibility of the tools by all medical staff may facilitate the general use of a potential interventional protocol.
Our study shows that malnourished patients have higher rates of treatment incompletion, regardless of the reason for termination, compared to patients with normal nutritional status. Lazarea et al. studied the reasons for premature discontinuation of curative radiation at different anatomical sites [8]. Based on 1001 HNC patients treated with curative intent, the treatment incompletion rate among this population was 5.8% and the main reason for early termination was discontinuation of medical advice [8] while medical advice ranked 2nd in the most common reasons in our study, accounting for 10 of 461 (2.2%) patients for CCRT incompletion. The apparent difference (0.8-1.2%) of CCRT incompletion rate between the two groups with respect to medical advice highlighted that malnourished patients were more vulnerable to treatment-related toxicity, deterioration of concomitant illness, and progression of cancer, compared to the normal nutrition population. On the other hand, patients will against medical advice is often multifactorial, involving concerns such as family support and socioeconomic issues [22]. As self-care is pertinent to any medical treatment [25,26], malnutrition may also help to identify patients who need social support.
The strength of this study lies in the large number of patients from multiple institutes, allowing the objective examination of the association between malnutrition and CCRT  Fig. 3 Causes of treatment incompletion of concurrent chemoradiotherapy treatment completion in HNC patients. Nevertheless, this study had several limitations. Firstly, this study did not investigate other commonly used nutritional assessment tools, such as the Glasgow prognostic score, Patient Generated Subjective Global Assessment, and prognostic nutritional index. Since the initiative of the study was to discover a convenient tool for nutrition evaluation, tools that require blood work or professional evaluation by the medical staff were excluded. However, these may also play a contributory role in nutritional evaluation. Secondly, nutrition is a dynamic status that may fluctuate prior to and during treatment. This raises two important issues among HNC patients undergoing CCRT. The first issue is whether the predefined timing for nutritional assessment is representative of a patient's nutritional status throughout the treatment trajectory. The second issue is w h e t h e r m a l n u t r i t i o n i s a n i r r e v e r s i b l e o r reversible condition in patients with HNC. While both issues cannot be answered directly by this study, our data emphasizes the importance of nutritional assessment in patients with HNC prior to CCRT. Further studies to examine the effect of aggressive nutritional intervention for patients with recognized malnutrition are warranted.

Conclusion
Malnutrition is prevalent among patients with HNC. The pretreatment nutritional status of HNC patients is related to the possibility of treatment incompletion and treatment-related toxicity. Nutritional tools such as MNA-SF, MUST, and NRS2002 are all competent tools for malnutrition recognition. We suggest that clinicians implement nutritional assessment prior to treatment to improve the chances of treatment completion for HNC patients with malnutrition.  Availability of data The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability Not applicable
Author contribution Conception and design of study: HSW, LCC, YKY, CHL, and WCC; Acquisition of data: TNM, SWH, HYS, and CPH; Analysis and interpretation of data: HCY, LYC, WCC, and TNM; Drafting of the manuscript: HSW, LCC, HCY, HYS, LCH, and WCC.

Declarations
Ethics approval This study was approved by the institutional review board of Chang Gung Memorial Hospital in August 2017 (ethic code: 1608080002) and has been conducted in compliance with the Helsinki Declaration (1996).
Consent to participate All patients provided written informed consent prior to inclusion.

Consent for publication Not applicable.
Competing interest The authors declare no competing interests.