Pattern of Nutritional status in Node Negative versus Node Positive Head and Neck Cancer patients undergoing treatment - a prospective cohort study

Abstract

Purpose

The aim of this study was to study the nutritional profile of node negative and node positive patients undergoing treatment for head and neck squamous cell cancer (HNSCC).

Methods

This prospective cohort study was conducted between 2018 and 2020. Patients diagnosed with HNSCC, planned for treatment were enrolled after written informed consent. In Node negative(N0) and Node positive(N+) cohorts of patients, nutritional status was determined using- anthropometric measures and Subjective Global Assessment (SGA) scale pre-treatment, during and after treatment. Statistical analysis was performed using SPSS version 22. Data was analyzed using parametric and non-parametric tests, p value of 0.05 was considered significant.

Results

161 patients were analyses, 73 N0 and 88 N+ cohorts. Pre-treatment, 9.6 to 20.4% patients in N0 and 23.9 to 32.8% patients in N+ cohorts were malnourished. Incidence of malnutrition at completion of treatment was 40.8–52.5% overall, 20.5–41.1% N0, 39.5–62.8% N+. Mean reduction in weight (11.1% ±7.82 v/s 6.26% ±8.3, p=0.000), mean reduction in BMI (2.57 ±1.87 v/s 1.29 ±1.62, p=0.000), median reduction in MUAC (2cm v/s 1cm, p=0.000) and median increase in SGA score were higher (13 v/s 6, p=0.000) in multi-modality as compared to single modality treatment. Similar findings were noted in N0 and N+ cohorts.

Conclusion

As compared to N0, N+ patients had higher burden of malnutrition at diagnosis, more worsening of nutritional parameters during treatment. More decline in Nutritional status was seen in patients receiving multi-modality as compared to single modality treatment.

Background

Head and Neck Squamous Cell Cancer(HNSCC) is the 6th most common cancer in the world, in 2018 there were 890,000 new cases and 450,000 deaths. The incidence is anticipated to increase by 30% by 2030 (Global Cancer Observatory (GLOBOCAN)) (1–3). In India the estimated age-standardized rate for incidence of HNSCC was >10.7 per 100,000 (GLOBOCAN 2018), in US this is 7.5-10.7 per 100, 1000. The high incidence in South-Asian region is associated with consumption of carcinogenic-containing products like oral tobacco, alcohol abuse and areca nut, whereas orophayngeal infection with HPV contributes to the high incidence in the West (4–6). HNSCC is treated with single modality or multimodality approach- surgical resection, radiation or chemotherapy plus radiation depending on the disease stage.

Malnutrition is seen in 30-50% of HNSCC patients; around 30% patients have severe malnutrition and weight loss since 6 months prior to diagnosis. Chemotherapy worsens the nutritional intake due to digestive tract related symptoms like loss of taste, mucositis, nausea and vomiting (7). Impairment related to swallowing and speech and xerostomia occur in ~50% of HNSCC patients following radiotherapy and these are often presistent long term (8). The 2-year prevalence of dysphagia in HNSCC survivors is 45%, this is 4-8 times more than those who never had cancer (9). Several studies have shown higher rates of treatment interruptions and less treatment effectiveness with high grade mucositis (10). Increased mortality and worse prognosis has been proposed to be associated with fat-free body mass loss related to malnutrition in cancer patients (11). Indian data on nutritional profile of patients undergoing treatment for HNSCC with regards to node negative and node positive cohorts is lacking.

The aim of this study was to study the nutritional profile of node negative and node positive patients undergoing treatment for head and neck squamous cell cancer (HNSCC).

Methods

This Prospective Cohort study was carried out at Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India between 2018 and 2020. Intsitiutional Ethics Committee clearance number- SRHU/HIMS/ETHICS/2018/115. The study population was patients starting treatment for HNSCC.

Inclusion criteria-

Patients with diagnosed and previously untreated HNSCC planned for treatment.

Exclusion criteria-

1. Previously treated for HNSCC with surgery, radiotherapy or chemotherapy.

2. Metastatic disease at presentation.

3. Patient with skin, nasopharynx or oesophagus cancer or with metastasis from primary sites other than head and neck.

5. Age less than 18 years.

Patients once diagnosed with HNSCC and planned for curative or palliative oncological treatment with single or multi-modality, were approached for enrollment in the study and an informed written consent was obtained. They were assessed for nutritional status before starting treatment, at end of each treatment modality and at completion of planned treatment. Following data was recorded-

a. Base line data regarding patient demographics, disease and treatment plan.

b. ECOG performance status (PS).

c. Nutritional status – Weight, Subjective Global Assessment (SGA) score, Mid-Upper Arm Circumference (MUAC), Body Mass Index (BMI) and Hemoglobin.

Based on the assumption that nutritional status may be different in patients with or without neck nodal metastasis, two cohorts were made based on the neck node status of the patient-

a. N0 cohort   - patients with no node metastasis at presentation

b. N+ cohort  - patients with node metastasis at presentation

The data was recorded, anonymised and analysed using following statistical methods.

Statistical Analysis-

The data was entered in MS Excel 2010. Statistical analysis was performed using SPSS software version 22. The one-sample Kolmogorov-Smirnov Test was used to determine whether data sets were different from normal distribution. Normally distributed data was analyzed using a Parametric tests- Unpaired student T test, Paired-sample T test; non-normally distributed data using Non-parametric tests- Mann-Whitney U test, Wilcoxon Signed Rank Test, Marginal Homogeneity Test and categorical data using Pearson Chi square test. The level of significance was taken as p<0.05.

Results

A total of 161 patients were enrolled in the study, 73 in N0 and 88 in N+ cohorts, 88.2% were male, mean age 56.32 (±13.27 SD) years, 60.8% in T3/4 stage, 40.4% patients received single modality and 59.6% multi-modality treatment. The pre-treatment mean weight was 57.75 (± 11.77 SD) Kg, BMI 21.58 (±4.2 SD), hemoglobin 13.42 (±1.77 SD) gm/dl, MUAC 24.71 (±3.78 SD) cm; the distribution of central tendencies of these parameters was similar in N0 and N+ cohorts. Pre-treatment mean weight loss in N0 and N+ cohorts was 4.25% and 7.93% (p=0.004), mean SGA score 36.95 and 42.74 (p=0.000) respectively (Table1). In N0 and N+ cohorts 13.7% and 28.4% (p=0.034) patients had lost more than 10% weight pre-treatment, 9.6% and 22.8% (p=0.036) patients had low MUAC, 10.9% and 27.2% (p=0.015) had SGA score of ≥50 and 4.1% and 18.2% (p=0.006) patients had bitot spots respectively (Table 2).

Discussion

The center where this study was conducted is a tertiary care cancer center, located at the foot of Himalayas in India. Approximately 1200 new cancer patients are treated at this center every year, 300 being Head and Neck cancer. The patients are usually from low to middle socioeconomic strata. The median age at diagnosis for non-HPV associated HNSCC is 66 years and HPV-associated oropharyngeal cancer is ~53 years in literature (12). In the present study, the mean age was 56.3 years, as in India, HNSCC is usually more non-HPV related, patients in this study were a decade younger. Majority patients in this study were T3/4 stage, this is in keeping with other reports (13), and required multi-modality treatment in ~60% patients. Malnutrition in head-neck cancer affects 30-50% of patients (10, 13). In a review article published in 2017 (14) it was noted that upto 80% of HNSCC patients are malnourished because of one their lifestyle and secondly the risk factors associated with HNSCC. In the present study among node negative patients, only 13.7% had lost the critical ≥10% weight within 6 months prior to starting treatment, only 10.9% had SGA score ≥50, only 9.6% had low MUAC and 20.4% patients had low BMI. Thus, 9.6 to 20.4% patients were observed to suffer from malnutrition at diagnosis in the node negative cohort. This is lower than the international literature. In node positive cohort, 28.4% patients had lost ≥10% weight within 6 months prior to starting treatment, 27.2% had SGA score ≥50, 32.8% had low MUAC and 23.9% low BMI. Thus, 23.9 to 32.8% patients were malnourished in node positive cohort at diagnosis. The burden of malnutrition was found to be higher in node positive patients; this could be due to multiple factors like- more advanced disease causing symptoms like swallowing or chewing difficulty, longer duration of disease with longer nutritional challenges, pain and other symptoms associated with advanced disease reduces oral intake. In HNSCC patients, cancer is close to structures vital for eating, leading to numerous nutritional challenges before, during and after treatment. They experience treatment side effects, like- odynophagia, dysphagia, xerostomia, dysgeusia, mucositis, sticky saliva, fatigue, nausea and vomiting (15). These further impair patient's ability to sustain adequate intake orally. A systematic review found ‘dysphagia’ to be the most commonly studied symptom during treatment for HNSCC (16). During or after treatment malnutrition and unintentional weight loss in HNSCC patients are associated with increased morbidity and mortality, poor treatment outcome and poor quality of life (17). The nutritional journey, as experienced by HNSCC patients undergoing treatment, may be different from the measured nutritional parameters. A qualitative study on 10 HNSCC patients undergoing treatment, aimed to study the experience of patients regarding their nutritional situation and perception of nutritional support during treatment. Patients experienced surgery as a poor starting point for Radiotherapy from nutritional aspect. Patients customized their diet as Radiotherapy started; they experienced virtually no oral food intake about halfway into Radiotherapy. This lead to tube-feeding and hospital admissions. All patients were recommended ONS, but supplements became unbearable eventually. After completion of Radiotherapy, patients experienced discouragement from persistent side effects, this prevented patients from eating (18).

The response to treatment, in HNSCC patients, is affected by their unique nutritional problems. To adequately manage these patients the treating team must accurately and systematically assess nutritional status and execute timely metabolic treatment (19). In the present study, all nutritional parameters declined significantly from baseline during the treatment. At the end of treatment, the mean reduction in weight was 9.17% (±8.33 SD) from baseline weight, ≥10% weight loss was present in 45.3% patients, low BMI 43.4% patients, low MUAC 40.8% patients, ≥50 SGA score 52.5% patients and moderate to severe anemia 16.9% patients. The incidence of malnutrition at completion of treatment in this study was 40.8–52.5% overall, in node negative cohort 20.5–41.1%, in node positive cohort 39.5–62.8%. In node positive cohort 15% more patients had low BMI, 19% more patients low MUAC, 23% more patients ≥50 SGA score at completion of treatment as compared to node negative cohort. Nutritional challenge for patients undergoing treatment for node positive HNSCC are far greater than node negative patients. A retrospective study published in 2019 aimed to assess the impact of prophylactic feeding gastrostomy (FG) and predictors of malnutrition in patients undergoing treatment for HNSCC (20). They studied 111 patients and found that patients without prophylactic FG had more hospital readmissions (p=0.042), greater relative weight loss at 6 weeks (p<0.0001), symptoms like dysphagia, higher rate of severe malnutrition. They found factors like Node positive status, oral intake difficulty, concomitant Chemo-radiotherapy, primary tumor sites like nasopharynx, and hypopharynx tumor site were significantly associated with malnutrition. A systematic review (21) published much prior (in 2013) analysed the effect of nutritional interventions like individualized dietary counseling, oral nutritional supplements (ONS), nasogastric (NG) tube feeding and percutaneous endoscopic gastronomy (PEG) on nutritional status, quality of life (QoL) and mortality in HNSCC patients receiving Radiotherapy or Chemo-radiotherapy. They found beneficial effects on nutritional status and QoL for individualized dietary counseling only; ONS, NG tube, PEG tube feeding were not consistently associated with benefit.

The detrimental effects of treatment for HNSCC on the nutritional status of a patient may vary according to the oncological treatment. Early stage HNSCC is usually treated with singly modality treatment like surgery or radiotherapy, whereas, locally advanced HNSCC is treated with multi-modality treatment like surgery followed by radiotherapy or chemo-radiotherapy or radical chemo-radiotherapy, depending on the location of primary tumor. Some patients, with locally advanced HNSCC, receive single modality treatment with a palliative intent. Nutritional parameters of single modality treatment and multi-modality treatment groups were compared in the present study. At completion of treatment we found that the ECOG performance status and mean weight were not different in both groups. But the mean reduction in weigh was 4.75% more, mean reduction in BMI was 1.28 kg/m² more, median increase in SGA score was 7 points more in multi-modality group as compared to single modality group (all statistically significant). Similar findings were noted in both node negative and node positive cohorts. In a prospective study published in year 2020 (22), patients undergoing single modality treatment with Radiotherapy for HNSCC were followed up for nutritional status and nutrition impact factors. Similar to the present study they used SGA score and found that 56% patients were malnourished at baseline and this increased to 100% after completion of treatment, the mean weight loss was 4.53 ±0.41 kg, 7.39%. They also reported taste changes and dry mouth in 100% patients. Another study published in the same year compared the health-related QoL in 19 HNSCC patients undergoing multi-modality treatment with Chemo-radiotherapy. They found that well-nourished patients had having fewer QoL issues like pain, sticky saliva, fatigue, chewing difficulty, appetite loss and social eating as compared to malnourished (p < .05). They found a statistically significant association (but weak strength, r = -0.37, P = .012) between global QoL score and SGA score (23). A randomized controlled trial (24) on HNSCC patients receiving Radiotherapy, compared nutritional counseling alone versus ONS along with nutritional counseling. ONS resulted in smaller weight loss (mean 1.6kg 95%CI 0.5-2.7, p=0.006), improved QoL and higher protein-calorie intake and reduced need for plan changes in oncological treatment (HR=0.40, 95%CI 0.18-0.91, p=0.029). The QoL of a patient is inter-related with psychological distress, an RCT aimed to improve the nutritional status of HNSCC patients receiving Radiotherapy, using psychological technique ‘Eating as Treatment’ (EAT) program, delivered by the dietitians. The control group had 151 patients and intervention group 156. SGA score was used to assess the primary end point- nutritional status. Intervention group had better SGA score, less percent weight loss, less treatment interruptions, lower depression scores and higher QoL (25). This RCT demonstrated effectiveness of psychological intervention (EAT) in improving nutrition in HNSCC patients undergoing treatment. The negative impact of treatment usually continues in the survivorship period too. In a qualitative study 31 HNSCC survivors were interviewed to acquire a comprehensive understanding of their lived experience of chronic Nutrition Impact Symptoms (NIS) burden (26). It was interesting to note, that they found at least one or more chronic NIS in all survivors, but before treatment 40% were unaware of the potential for chronically persistent NIS. The present study highlights the need for supportive therapies in cancer care, especially nutritional services. Low and middle income countries like India face disparities in health care systems with regards to these supportive care services. There are limitations in availability of nutrition specialists, cancer dieticians and even nutritional supplements in low cost cancer centers, where majority of cancer patients are treated.

In 2016 “Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines” were published (27). The following recommendations were made regarding treatment of HNSCC-

• The multidisciplinary team should include a specialist dietitian.

• Nutritional assessment should be performed using a validated tool before starting treatment and at regular intervals.

• High risk patients should be referred for early dietary intervention.

• Appropriate nutritional support and malnutrition treatment should be offered without delay.

• They recommended SGA and Patient Generated SGA as validated tools for nutritional assessment.

• Pre-treatment nutritional assessment should be offered.

• Patients well nourished pre-treatment should receive regular dietary assessment and intervention.

• They recommended energy intake of minimum 30kcal/kg/day and protein intake 1.2g/kg/day.

• Enteral nutrition to be started in the food intake is <60% of the estimated energy expenditure.

• Gastrostomy is recommended over NG tube if long-term (4 weeks) tube feeding is anticipated.

• Nutritional interventions like dietary counseling and diet supplements should be offered upto 3 months after treatment.

• QoL parameters related to nutrition should be estimated pre-treatment, during treatment and post-treatment at regular intervals.

In conclusion, HNSCC patients may be malnourished at presentation, and the nutritional status deteriorated in a vast proportion of patients during treatment. Node positive patients had a higher burden of malnutrition at diagnosis, higher worsening of nutritional parameters during treatment as compared to Node negative patients. A higher decline in Nutritional status was seen in patients receiving multi-modality as compared to single modality treatment. Thus, Node positive HNSCC patients receiving multi-modality treatment have the highest burden of malnutrition.

Declarations

Funding: The authors have no relevant financial or non-financial interests to disclose.

Conflicts of interest/Competing interests: The authors have no competing interests to declare that are relevant to the content of this article. 

Availability of data and material:      available

Code availability:              SPSS version 22

Authors' contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Anshika Arora, Sunil Saini and Meenu Gupta. The first draft of the manuscript was written by Anshika Arora and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval: Ethics committee approval number-   SRHU/HIMS/ETHICS/2018/115

Consent to participate: A written informed consent was obtained from all participants 

Consent for publication: Consent for publication was obtained from the Institutional Research Committee.

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