Running head: SCCHN & WEIGHT 1

Impact of Squamous Cell Carcinoma of the Head/Neck (SCCHN) on Weight Status

Abigail Smith

University of Kentucky

SCCHN & WEIGHT 2

Abstract

The purpose was to examine the impact of diagnosis and treatment of squamous cell

carcinoma of the head/neck (SCCHN) on weight status over a 5-week period. A sample of

25 SCCHN patients treated with radiation therapy for a minimum of 5 weeks was

retrospectively analyzed. Comparison of the mean weight change over the 5-week period

did not yield statistically significant results (p=0.72). The average weight loss over 5 weeks

was 3.12% (2.38 kg). Multiple linear regression examining the association between

explanatory variables – age, gender, tumor site – and the response variable – percent

weight change – explained 13.44% of weight change in this population (R2 =0.13442). Each

additional year of age was associated with a 0.087% weight loss (p=0.13). Men were

associated with 2.19% less weight loss over 5 weeks than women (p=0.38). Oral tumor site

was associated with a 3.05% greater weight loss over 5 weeks when compared to other

tumor H/N tumor sites (p=0.058). Though results did not reach statistical significance, this

study suggests substantial clinical implications. Data regarding the anticipated average

weight loss and risk factors for increased weight loss in HNC patients could be used to

guide healthcare professionals and caregivers in choosing an optimal prophylactic

nutrition strategy.

SCCHN & WEIGHT 3

Impact of Squamous Cell Carcinoma of the Head/Neck (SCCHN) on Weight Status

Review of Literature

Introduction

Cancer is the second leading cause of death in the United States; 1,630 people die of

cancer every day (American Cancer Society, 2016). In 2016, there is projected to be an

estimated 1,685,210 new cancer cases and 595,690 deaths from cancer in the United

States. Of these, an estimated 48,330 new cases and 9,570 deaths will be comprised of

head and neck cancer (HNC) diagnoses (Siegel, Miller, & Jemal, 2016). The National Cancer

Institute cited a significant increase in head and neck cancer cases from 1983-2002

(National Cancer Institute, 2013). From 2003-2012, the instance of head and neck cancer,

specifically oral cavity and pharynx (throat) increased by 1.3% per year, or 11.7% over 9

years, in white males (American Cancer Society, 2016). Squamous cell carcinoma accounts

for 40% of HNC cases (Mignogna, Fedele, & Lo Russo, 2004).

HNC is typically detected at a more advanced stage, which leads to poorer outcomes

(Mignogna et al., 2004). Survival rate varies substantially by stage at diagnosis as well as

the site of the tumor. Lip tumor is associated with a 90% survival rate, salivary gland 73%,

floor of mouth 51%, and hypopharynx 32% (American Cancer Society, 2016).

Treatment

HNC causes noticeable symptoms that impair normal function including dysphagia,

aspiration, vocal changes, and pain (List & Bilir, 2004). About 50% of patients express pain

related to their HNC diagnosis prior to any treatment. However, the treatment of HNC

brings about even more side effects than the cancer itself. Approximately 81% of patients

express pain during treatment. A number of treatment regimens are used to irradiate HNC,

SCCHN & WEIGHT 4

including surgery, radiation therapy, chemotherapy, and a combination thereof. The most

common treatment complications are mucositis, infection, salivary gland dysfunction, taste

dysfunction, and pain, which lead to secondary complications such as dehydration,

dysgeusia, and malnutrition (National Cancer Institute, 2016).

The most common treatment for HNC is radiation therapy (Department of Health

and Human Services, 2015). Radiation often leads to complications such as xerostemia

(>66% of patients), difficulty eating/swallowing (~35-68%), sticky saliva (~33%), pain

(~15-30%), and change in appearance (~20-25%), among others (List & Bilir, 2004).

Difficulty chewing and swallow dysfunction are the most common complications associated

with radiation therapy for treatment of SCCHN, occurring in at least 2/3 of patients (Silver

et al., 2010). Significant oral and nutritional problems occur in up to 80% of patients

treated with radiation therapy (List & Bilir, 2004).

Weight Loss

Studies have documented the weight loss associated with treatment of HNC. Platek

et al. (2013) retrospectively compared the weight status and loco-regional SCCHN

progression of two cohorts treated with concurrent chemoradiation therapy (CCRT). Both

cohorts experienced an overall average weight loss of 9% over the 7-week treatment

period. This weight loss was attributed to dysphagia, xerostemia, radiation-induced

mucositis, and other CCRT-related toxicities. There were no significant differences between

the two cohorts despite the provision of nutritional intervention to the treatment cohort

(Platek et al., 2013).

Silver et al. (2010) observed SCCHN patients throughout treatment with CCRT and

post-treatment follow-ups to identify predictors of functional decline. Patients experienced

SCCHN & WEIGHT 5

approximately 12% loss of total body mass averaging 13.1 ± 11.2 kg over a 6-month

period. Significantly large losses in mid-arm, mid-calf, and waist circumference were also

noted. The study identified four main factors associated with functional decline: difficulty

chewing and/or swallowing, weight loss, fatigue, and perceived stress (Silver et al., 2010).

A comprehensive literature search identified numerous risk factors for weight loss

associated with HNC and its treatment. The top three risk factors identified by this study

were advanced tumor stage, higher BMI before treatment, and the use of CCRT. Advanced

tumor stage was found to be an independent risk factor for weight loss. Although not an

independent risk factor, patients with an overweight/obese BMI classification experienced

significantly greater weight loss than patients with a normal or underweight BMI (Zhao,

Zheng, Li, Zhang, Zhao, & Jiang, 2015).

Importance of Nutrition

Malnutrition occurs in approximately 80% of cancer patients at some time during

treatment. Poor nutritional status during treatment is associated with increased morbidity

and mortality. Further, markers of malnutrition including weight loss and low muscle mass

index are predictive of patient survival. Weight loss of as little as 5% decreases survival

rate (Oncology Nutrition, 2014). Weight loss exceeding 5% within 3-12 months combined

with symtpoms including fatigue, loss of skeletal muscle, and biochemical abnormalities is

defined as cachexia. Cancer cachexia is the third most frequent subtype based on

population prevalence; 60-80% of patients with advanced cancer have cachexia. Within

the cancer population, more than 30% of patients die due to cachexia and 50% of patients

die with cachexia present. There is an 80% mortality rate of patients with cancer cachexia

(Von Haehling & Anker, 2010).

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Malnutrition also restricts patient ability to proceed with cancer treatment and

reduces overall quality of life. Continued malnutrition following completion of cancer

treatment increases the risk of cancer recurrence (Oncology Nutrition, 2014).

Cancer patients have increased energy and protein requirements due to a higher

resting metabolic rate as a result of disease state and/or treatment. Increasing energy and

protein intake can help prevent weight loss and loss of muscle mass (Gullett, Mazurak,

Hebbar, & Ziegler, 2011). However, disease and treatment related complications

frequently prevent adequate oral intake (List & Bilir, 2004). For these reasons,

multidisciplinary approaches to cancer treatment include registered dietitians to minimize

weight loss and educate patients on the importance of good nutrition throughout treatment

(Department of Health and Human Services, 2015).

Conclusions

HNC alone, and in conjunction with its treatment complications, causes significant

nutritional problems including severe weight loss. Malnutrition and weight loss are

associated with a decrease in patient survival rate. Studies have identified predictors of

increased weight loss, however, no nutritional interventions have shown a statistically

significant difference in preventing weight loss. With the continuing increase in new cases

and deaths from HNC, it is clear that HNC is a rising concern that warrants additional

research. Given the proven importance of nutrition during cancer treatment and the

documented weight loss HNC patients experience, efforts should be focused on preventing

malnutrition and weight loss within this population.

SCCHN & WEIGHT 7

Hypothesis

Individuals diagnosed with and treated for squamous cell carcinoma of the head/neck

(SCCHN) will experience significant weight loss within the first 5 weeks of treatment with

radiation therapy.

SMART Objectives

Measure the average weight change of individuals treated for squamous cell carcinoma of the

head/neck within the first 5 weeks of treatment with radiation therapy. Identify risk factors for

increased weight loss in individuals treated for squamous cell carcinoma of the head/neck during

treatment with radiation therapy.

Methodology

Design and Setting

This retrospective observational study of SCCHN patients was reviewed and approved by

the Psychology-Oncology Department at the University of Kentucky Markey Cancer Center in

Lexington, Kentucky. Patients diagnosed with an oral or throat squamous cell carcinoma tumor

and treated with radiation therapy for a minimum of 5 weeks at the time of data collection were

eligible for this review.

Outcomes Collected

Retrospective patient information was collected from the paper medical records available

in Radiation Medicine at the UK Markey Cancer Center which included the following: age at

diagnosis, gender, tumor site, tumor stage, height and weight, and the type of tube feeding if

applicable. Not all patient medical records included complete information. Of the 25 records

reviewed, 5 did not contain tumor stage and 7 did not include height. Measurements of body

weight were collected bi-weekly throughout the 5-week treatment observation period.

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Weight change over the 5-week period was calculated by subtracting starting weight from

ending weight, measured in kilograms. Percent weight change was calculated by dividing weight

change in kilograms by starting weight in kilograms and multiplying by 100. Body mass index

(BMI) was calculated as weight in kilograms divided by height in meters squared using both

starting weight and ending weight. BMI change over the 5-week period was calculated by

subtracting starting BMI from ending BMI.

Statistical Analysis

The statistical package for Excel 2011 for Mac StatPlus: Mac LE (Build 6.0.3) was used

for all statistical analyses. The t-test assuming unequal variances (heteroscedastic) for comparing

means was used to examine the statistical significance of the observed weight change. Multiple

linear regression was used to examine the strength of relationship between predictors – age,

gender, tumor site – and the response variable – percent weight change. A p value of <0.05 was

considered statistically significant.

Results

Twenty-five SCCHN patients treated with radiation therapy at the UK Markey

Cancer Center were examined. An examination of weight change over the 5-week

treatment period did not yield statistically significant results. The average starting weight

was 82.54 kg. The average ending weight was 80.16 kg. The average weight change in the

5-week period was a loss of 2.38 kg. The average percent weight loss was 3.12%. Figure 1

provides a comparison of the average starting weight and average ending weight. The

sample means t-test for comparing the mean starting and ending weight (kg) resulted in a p

value of 0.72.

SCCHN & WEIGHT 9

Figure 1: Comparison of average starting and ending weights

Table 1 provides descriptive characteristics for the population studied. The median

age of the patient population was 58.52 years. Of the 25 patients, 12 had a tube placed for

feeding, the most common type being a PEG tube.

Tumor site was refined for analysis and classified as “oral” if the tumor was located in the

oral cavity or “other” if it was otherwise located. Within this patient population, 32%

(8/25) of tumors were orally located.

Table 1: Population descriptive characteristics

Characteristics, n=25

Average age in years at diagnosis 58.52 Gender, male/female 23/2 Tumor site, oral/other 8/17 Average starting weight in kg 82.54 Average ending weight in kg 80.16 Tube feeding, yes/no 12/13

Within the population for which tumor staging was available, tumor progression

was classified as advanced if the TNM staging included an “N” of 1 or greater, indicating the

82.54

80.16

78.5

79

79.5

80

80.5

81

81.5

82

82.5

83

Starting Weight Ending Weight

We

igh

t (k

g)

SCCHN & WEIGHT 10

presence of lymph involvement. Of the 20 patients with staging information available, 60%

(12/20) had advanced tumor progression.

Of the population for which BMI information was available (n=18), 6% were

underweight (BMI <18.5) before treatment, 50% were normal weight (BMI 18.5-24.5), and

44% were overweight or obese (BMI >25). Median starting BMI was 23.8.

Multiple linear regression examined the association between explanatory variables

– age, gender, tumor site – and the response variable – percent weight change. Table 2

provides the results of the linear regression by variable. The linear regression model run in

this study using the aforementioned explanatory variables explained 13.44% of weight

change in this population (R2 =0.13442). Within the regression, each additional year of age

was associated with a 0.087% weight loss. Though this was not statistically significant

(p=0.13). Men were associated with 2.19% less weight loss over 5 weeks than women

though this was also not statistically significant (p= 0.38). Oral tumor site was associated

with a 3.05% greater weight loss over 5 weeks when compared to other tumor head and

neck tumor sites (p=0.058).

Table 2: Multiple linear regression by variable

Variables Effect on % Weight Change p value

Age 0.087% more weight loss in 5 weeks per year of age

0.13

Gender 2.19% less weight loss in 5 weeks associated with males compared to females

0.38

Tumor Site 3.05% more weight loss in 5 weeks associated with oral tumor compared to other H/N tumor sites

0.058

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Discussion

Statistical Analysis

In this sample of patients treated with radiation therapy for SCCHN, weight change

over the 5-week week period was not statistically significant. However, the mean weight

loss of a 3.12% has clinical significance. Cachexia is defined as weight loss exceeding 5%

within 3-12 months (Von Haehling & Anker, 2010). Given the shorter time period studied

and the location early within the radiation cycle, the observed weight change is indicative

of likely cachexia status. More than 30% of cancer patients die due to cachexia and 50% of

patients die with cachexia present (Von Haehling & Anker, 2010). Additionally, cachexia

and malnutrition limit patient ability to proceed with cancer treatment and reduce overall

quality of life. Continued malnutrition and weight loss following treatment increase the risk

of cancer recurrence (Oncology Nutrition, 2014).

Multiple linear regression examined the association between explanatory variables

– age, gender, tumor site – and the response variable – percent weight change. In this

analysis, increased age was associated with an increased weight loss. Each additional year

of age was associated with an additional 0.087% weight loss. However, this was not

statistically significant (p=0.13). This association may be due to a number of reasons

related to advanced age including food insecurity and diminished health status

independent of cancerous state.

Within the regression model, there were gender differences in weight change over

the observed 5-week period. Men were associated with 2.19% less weight loss over a 5-

week period than women, though this was also not statistically significant (p= 0.38). In

other words, women were associated with a 2.19% greater weight loss than men in 5

SCCHN & WEIGHT 12

weeks. Zhao et al. (2015) identified female sex as a risk factor for increased weight loss in

HNC patients (Zhao et al., 2015).

In this analysis, oral tumor site was associated with a 3.05% greater weight loss

over 5 weeks as compared to other head and neck tumor sites (p=0.058). Although this

association did not reach statistical significance (p<0.05), it came very close. This finding is

consistent with research, which named oral cavity tumor site as a risk factor for increased

weight loss in HNC patients (Zhao et al., 2015).

An earlier regression model also examined the presence/absence of tube feeding,

tumor progression, and starting BMI as explanatory variables associated with percent

weight change. However, when these variables were included in the analysis, p values

increased, meaning they were farther from reaching statistical significance.

Limitations

The small sample size (n=25) is largely responsible for the high p values associated

with analyses in this study. There was a short period allotted for data collection (7 weeks)

and limited access to medical records, which reduced the quantity of data collected. Unless

H0 is true, a larger sample size is associated with a smaller p value because uncertainty

decreases with an increased sample size.

Some patients were still receiving treatment when data was collected and therefore,

their medical records do not show the full timeline of their treatment from start to finish.

These incomplete records were still used in this analysis due to the difficulty of obtaining

data. According to Silver et al. (2010), the most significant weight loss occurs beginning

around weeks 3-5 of treatment and weight loss continues for around 6 months following

treatment (Silver et al., 2010). Due to the availability of patient records, only the first 5

SCCHN & WEIGHT 13

weeks of treatment were examined. This limitation further explains why the observed

weight loss did not reach statistical significance.

Incomplete patient records caused other errors in this study. Within patient medical

records, weight measurement was not always labeled as “pounds” or “kilograms” so the

researcher’s best guess was used. Height was not always recorded. This prevented the

calculation of BMI. Zhao et al. (2015) identified a higher pre-treatment BMI as a strong

predictor of increased weight loss in HNC patients (Zhao et al., & Jiang, 2015). However,

when this variable was included in the regression model, n was decreased to 18 due to the

lack of available height – and subsequently BMI – information for the total population of

n=25. As previously explained, this decreased n resulted in increased p values. Similarly,

tumor staging was not always recorded which prevented the determination of tumor

progression. Zhao et al. (2015) also identified advanced tumor stage as an independent

predictor of increased weight loss in HNC patients (Zhao et al., 2015). When this variable

was included in the regression model, n was decreased to 20 due to lack of available

staging data for the total population of n=25 which consequently decreased the resulting p

values. Finally, treatment details including duration, strength, target area, and concurrent

therapies (i.e. surgery and chemotherapy) were unavailable in the paper medical records

obtained from the Radiation Medicine Department. Zhao et al. (2015) identified a higher

radiation dose, presence of radiation on neck nodes, and accelerated radiation treatment

schedule as risk factors for increased weight loss in HNC patients (Zhao et al., 2015). Platek

et al. (2013) found that a decreased treatment time was associated with a decrease in

weight loss (Platek et al., 2013). Since this treatment information was not available, it was

not included the analyses.

SCCHN & WEIGHT 14

Zhao et al. (2015) named absence of tube feeding at the start of radiation therapy as

a risk factor for increased weight loss in HNC patients (Zhao et al., 2015). In this study, the

presence or absence of tube feeding was noted when included in patient medical records.

However, due to the retrospective observational nature of this study, it was impossible to

determine if tube feeding was used during treatment period examined (first 5 weeks) and if

patients utilized tube feeding at all (noncompliance issues). Therefore, the

presence/absence of tube feeding was not included in the regression analysis, although

there is reason to believe the presence of tube feeding is associated with decreased weight

loss.

Future Research

Despite the lack of statistical significance resulting from this study, these findings

should encourage additional research in this area, potentially using a similar model to

explore these results more thoroughly. Future studies should examine a larger sample size.

Research design may be altered to follow patients as they are receiving treatment and for

approximately one year post-treatment to monitor ongoing weight changes, cancer

recurrence, and death. This would also allow researchers to more closely monitor the use

of tube feeding for a more accurate analysis of this variable. Research in a setting with

more support from oncology doctors, nurses, and dietitians would also be beneficial

because records would contain more complete information (i.e. height, tumor staging, etc.)

needed for a more complete analysis.

Clinical Implications

The results of both this study and proposed future studies could have substantial

clinical implications. Information regarding the anticipated average weight loss and risk

SCCHN & WEIGHT 15

factors for increased weight loss in HNC patients could be used to guide healthcare

professionals and caregivers in choosing an optimal prophylactic nutrition strategy based

on the presence or absence of these risk factors. Earlier and more effective nutrition

interventions may lessen the effects of cancer cachexia or prevent it altogether, thereby

improving prognosis and increasing survival rate (Oncology Nutrition, 2014).

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