Download Relationship of protein and calorie intake to the severity of oral

ORIGINAL ARTICLE
RELATIONSHIP OF PROTEIN AND CALORIE INTAKE TO THE
SEVERITY OF ORAL MUCOSITIS IN PATIENTS WITH HEAD
AND NECK CANCER RECEIVING RADIATION THERAPY
Karen L. Zahn, MS,1 Gene Wong, MD,2 Edward J. Bedrick, PhD,3 Deborah G. Poston, MS,4
Thomas M. Schroeder, MD,5 Julie E. Bauman, MD6
1
Department of Internal Medicine, Senior Clinical Nutritionist University of New Mexico Cancer Center, Albuquerque,
New Mexico. E-mail: [email protected]
2
Radiation Oncologist, Lahey Clinic, Burlington, Massachusetts
3
Department of Internal Medicine, Division of Biostatistics, University of New Mexico Health Sciences Center, Albuquerque,
New Mexico
4
Nursing Department, University of New Mexico Cancer Center, Albuquerque, New Mexico
5
Radiation Oncologist, Department of Internal Medicine, Division of Radiation Oncology, University of New Mexico Cancer
Center, Albuquerque, New Mexico
6
Department of Internal Medicine, Division of Hematology/Oncology University of New Mexico Cancer Center, Albuquerque,
New Mexico
Accepted 22 February 2011
Published online 20 June 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21795
Abstract: Background. The purpose of this study was to
evaluate the relationship of calorie and protein intake to the severity of oral mucositis in patients with head and neck cancer
receiving radiation therapy.
Methods. Patients with head and neck cancer undergoing
60 Gy of radiation were eligible. Weekly data were collected
for oral mucositis grade and protein and calorie intake. Proportional odds models examined the association of oral mucositis
severity with nutritional predictors.
Results. During a 24-month period, 40 evaluable patients
met criteria for inclusion. In a multivariate backward selection
model, the sole significant nutritional predictor of reduced oral
mucositis severity was meeting the protein goal for the current
week (p ¼ .01; adjusted odds ratio [OR], 2.30).
Conclusion. Patients who met protein-related goals during
radiotherapy for head and neck cancer had less severe oral
mucositis. Nutritional counseling during radiotherapy, with emphasis on protein goals, may reduce oral mucositis severity.
C 2011 Wiley Periodicals, Inc. Head Neck 34: 655–662, 2012
V
Keywords: mucositis; protein; nutrition; head and neck cancer;
radiation
An estimated 58,540 men and women in the United
States were projected to be diagnosed with head and
neck cancer in 2009.1 Based on data from 2002 to
2006 the incidence for all races ranges from 4.2 to
15.4 per 100,000, depending on anatomic site within
Correspondence to: K. L. Zahn
This research was unfunded; it was supported by the University of New
Mexico Cancer Center, Albuquerque, New Mexico.
C 2011 Wiley Periodicals, Inc.
V
Nutrition Intake Related to Oral Mucositis
the head and neck.1 Radiation therapy is a critical
component of the modern, multimodality management of head and neck cancer. The current standard
of care is to deliver 60 to 72 Gy to the areas at risk,
either in the postoperative or definitive setting.
Radiotherapy treatment intensification, such as with
altered fractionation or concurrent chemotherapy,
increases locoregional disease control and head and
neck cancer survival.2,3 However, improved oncologic
outcomes come at the expense of heightened treatment-related toxicity. In particular, radiation has a
cumulative negative effect on the mucosal lining of
the oral cavity, oropharynx, and hypopharynx, resulting in inflammation and ulceration conventionally labeled ‘‘oral mucositis.’’ Given that oral mucosa is an
intrinsic part of the targeted anatomy, oral mucositis
in head and neck cancer is unavoidable, and is seen
in virtually all patients undergoing radiation.4–6 Oral
mucositis can progress from asymptomatic erythema
to mildly painful patchy pseudomembranes to acutely
painful confluent pseudomembranes and ulcerations.7
In patients with head and neck cancer undergoing
radiation treatment, symptomatic oral mucositis
accounts for the majority of treatment interruptions,
which results in excess hospitalizations, and is associated with higher treatment costs.6,8 Patients with
oral mucositis are 4 times more likely to have
unplanned breaks in radiation therapy.4 Treatment
interruptions permit clonogenic tumor cell repopulation and are associated with decreased locoregional
control and survival rates.9–11 Thus, clinical strategies which prevent, decrease severity of, or attenuate symptoms of oral mucositis are paramount to
optimizing quality of life and disease outcomes.
HEAD & NECK—DOI 10.1002/hed
May 2012
655
Nutritional intake during radiation may impact
the severity of oral mucositis because it is known to
be an important factor in wound healing. Wound
healing depends on the presence of adequate
nutrients, including protein and energy, to provide for
tissue repair.12,13 Even mild protein-energy malnutrition of short duration can negatively affect wound
healing.14 Delays in wound healing associated with
malnourishment seem to occur early in the course of
protein-energy malnutrition, before there is even a
change in anthropometrics.14 In surgical patients,
adequate food intake within the preoperative week
maintains wound healing, regardless of anthropometric nutritional status, whereas inadequate food intake
1 week before surgery impairs wound healing.15
We hypothesized that current poor nutritional
intake reduces the ability to maintain mucosal integrity or to repair acute mucosal injury sustained during radiation treatment, resulting in more severe oral
mucositis. In particular, inadequate protein intake
may deplete an essential, unstored nutrient critical
for ongoing mucosal repair in the face of daily injury.
This prospective, single arm, descriptive study
was designed to evaluate the relationship of current
calorie and protein intake to the severity of oral
mucositis in patients with head and neck cancer
receiving radiation therapy.
MATERIALS AND METHODS
The Institutional Review Board at the University of
New Mexico (UNM) granted approval of this study in
September 2006, and written informed consent was
obtained from all patients.
Consecutive patients referred to the Radiation
Oncology Clinic at the UNM Cancer Center were
considered for enrollment if they met the following
criteria: (1) diagnosis of a head and neck cancer with
confirmed histology of squamous cell carcinoma, adenocarcinoma, or salivary gland carcinoma; (2)
planned radiation dose 60 Gy; (3) primary tumor
site within the oral cavity, oropharynx, hypopharynx,
larynx, nasal cavity, paranasal sinuses, major salivary glands, or unknown primary; and (4) age 18
years old. Patients could be entered into the study
either before or during the first week of radiation
treatment.
Radiation was administered using 6MeV photons
with a linear accelerator. Inverse-planned intensity
modulated radiotherapy (IMRT) was used with a
step-and-shoot technique for the first 25 patients in
the study and with dynamic helical tomotherapy for
the last 15 patients in the study. Although not specified in the protocol, generally 2 fractionation regimens were used. A sequential boost technique was
used with step-and-shoot IMRT, in which subclinical
disease received 50 Gy in 25 fractions of 2 Gy, followed by a boost to gross disease or postoperative bed
with the total prescribed dose being between 60 to 70
656
Nutrition Intake Related to Oral Mucositis
Gy in 5 to 10 fractions of 2 Gy depending on the clinical scenario. An integrated boost technique was used
with helical tomotherapy in which subclinical disease
was treated to a dose of 54 Gy in 30 fractions of 1.8
Gy, whereas the postoperative bed and/or gross disease was treated concurrently to a dose of 60 to 66
Gy in 30 fractions of 2 to 2.2 Gy depending on the
clinical scenario.
At study entry, the following demographic and baseline data were collected: age, sex, ethnicity, height,
weight, head and neck surgical history, primary cancer
site, TNM classification based on the American Joint
Committee on Cancer Staging Manual,16 total radiation
dose, type of radiation, and chemotherapy regimen.
The use of induction or concurrent chemotherapy was
deferred to the treating medical oncologist and regimens were not specified in the protocol. Medical oncology care was delivered at UNM and 1 outside practice
setting which contracted with the UNM Radiation Oncology service. Both induction and concurrent chemotherapy regimens were recorded in detail. For purposes
of analysis, induction chemotherapy was bivariate (yes
or no). Concurrent chemotherapy regimens were categorized into the following groups, in accordance with
known synergistic toxicity to mucosa during chemoradiation: 1, none; 2, cetuximab or single agent chemotherapy; or 3, high dose cisplatin or 2 or more
chemotherapy agents.
Patients completed the Patient Generated Subjective Global Assessment (PG-SGA)17 and the Global
Assessment of nutritional status was scored. The
PG-SGA is a validated nutritional assessment tool,
which includes information about recent weight loss,
food intake and route of intake, symptoms which
may interfere with normal food intake, and level of
activity as determined by the patients. This information generates a score describing patients’ baseline
nutritional status. Enteral feeding was also noted at
baseline. The registered dietitian assessed each
patient’s current nutritional intake and nutritional
requirements during treatment. Actual body weight
during the first week of treatment was used to calculate baseline calorie and protein requirements,
according to the theoretical requirements of a
stressed patient with cancer: 35 kilocalories per kilogram (kg) and 1.5 grams protein per kg.18 All
patients received the same study information packet
including nutritional materials, oral care checklist,
and weekly food records. The registered dietitian
conducted one-on-one counseling for nutritional
intake and hydration goals and educated patients on
how to fill out the food records and oral care checklist. Oral care education was standardized to include
promoting active self-care, taking in adequate food
and fluid, brushing and rinsing of the oral cavity,
use of ‘‘magic mouthwash’’ (nystatin or magnesium
hydroxide, lidocaine 1%, and dephenhydramine in a
ratio of 1:1:1), and avoidance of irritants to the oral
mucosa.19
HEAD & NECK—DOI 10.1002/hed
May 2012
Death
Symptomatic and unable to
adequately aliment or hydrate
orally; respiratory symptoms
interfering with ADL
Eat and swallow modified diet; respiratory
symptoms interfering with function
but not interfering with ADL
Minimal symptoms, normal diet;
minimal respiratory symptoms
but not interfering with function
Functional symptomatic
Nutrition Intake Related to Oral Mucositis
The study used a prospective longitudinal design with repeated intra-subject
measurements to assess factors influencing the severity
of oral mucositis among patients with head and neck
cancer undergoing radiation. Nutritional variables
potentially influencing the severity of oral mucositis
were categorized as follows: (1) meeting calorie goals
for the current week; (2) meeting calorie goals for the
prior week; (3) meeting calorie goals for both the current and prior week; (4) meeting protein goals for the
current week; (5) meeting protein goals for the prior
week; (6) meeting protein goals for the current and
prior week; (7) meeting both calorie and protein goals
for the current week; (8) meeting both calorie and protein goals for the prior week; and (9) meeting both calorie and protein goals for the current and prior week.
Nutritional goals were considered met at 100% or
greater of the calculated needs. A proportional odds
model was planned due to its power to summarize the
effect of a single variable on the severity of oral mucositis, regardless of the defined cut point for ‘‘severe,’’ by
integrated analysis of 3 potential cut points. Cut points
corresponded to the oral mucositis grading system in
the National Cancer Institute CTCAE.20 An unadjusted, proportional odds model was fit for each nutritional goal to determine association with severity of
oral mucositis. Each model was then adjusted for variables potentially associated with severity of oral mucositis, including anatomic site, TNM classification, age,
current alcohol and tobacco use at baseline, nutritional
status (PG-SGA), oral versus enteral feeding at baseline, type of radiation, concurrent chemotherapy, and
time on treatment. Due to presumed high correlation
among the nutritional goals, a multivariate backward
selection model was created to identify the most important nutritional predictors of oral mucositis severity.
A sample size of 40 patients was selected for the
study. The power calculation was based on the
assumption that the difference between the
Statistical Considerations.
Abbreviations: ADL, Activities of Daily Living.
Death
Tissue necrosis; significant
spontaneous bleeding;
life-threatening
consequences
Symptoms associated with
life-threatening consequences
Mucositis clinical examination
Erythema of the mucosa
Patchy ulcerations or pseudomembranes
Confluent ulcerations or
pseudomembranes; bleeding
with minor trauma
5
4
3
2
1
Table 1. Common toxicity criteria for adverse events v 3.0 criteria for mucositis grading.20
Patients were seen weekly in the radiation oncology clinic. At each visit, they were weighed using the
same scale. Oral mucositis and dysphagia were evaluated and graded according to the National Cancer
Institute guidelines using the Common Terminology
Criteria for Adverse Events, version 3 (CTCAE v.
3).20 Oral mucositis grading, based on the CTCAE v.
3, is presented in Table 1.
Each week, a 1-day food record or 24-hour food
recall was obtained and reviewed in detail for completeness with the registered dietitian. Patients were
asked to record a day representative of the week’s
intake, specifically a weekday in which chemotherapy
was not administered. Food records were analyzed
using Nutritionist Pro software (Nutritionist Pro,
Axxya Systems). Total calories and protein were
recorded weekly for the same numbered week as the
oral mucositis and dysphagia grades.
HEAD & NECK—DOI 10.1002/hed
May 2012
657
Table 2. Patient characteristics (n ¼ 40).
No. of patients (%)
Sex
Female
Male
Ethnicity
White
Hispanic
Native American
Anatomic site
Lip/oral cavity
Pharynx (including base of tongue)
Larynx
Nasal cavity/paranasal sinuses
Salivary glands
Unknown primary
TNM classification20
I
II
III
IV
Unknown/missing data
Radiation type
Step-and-shoot IMRT
Helical tomotherapy
Induction chemotherapy
None
Yes
Type of chemotherapy during radiation
None
Single agent cetuximab or taxol
Platinum or 2 or more chemotherapy drugs
PG-SGA17
Well nourished
Moderate malnutrition
Severely malnourished
10 (25.0)
30 (75.0)
29 (72.5)
9 (22.5)
2 (5.0)
7
20
7
2
3
1
(17.5)
(50.0)
(17.5)
(5.0)
(7.5)
(2.5)
0
2
12
23
3
(0.0)
(5.0)
(30.0)
(57.5)
(7.5)
25 (62.5)
15 (37.5)
19 (47.5)
21 (52.5)
7 (17.5)
5 (12.5)
28 (70.0)
31 (77.5)
9 (22.5)
0 (0.0)
Abbreviations: IMRT, intensity-modulated radiation therapy; PG-SGA, Patient Generated Subjective Global Assessment.
probabilities of less severe oral mucositis for patients
that did and did not meet a specific nutrition goal
could be as large as 0.20. In a repeated measures
study with 6 responses per patient, a 5% test of no
association has 80% power to detect a 0.20 difference
with 23 to 56 patients, provided the individual correlation between responses is less than 0.50.21 Our protocol called for at least 6 measurements on each
patient, thus a projected sample size of 40 patients
would suffice to identify a clinically relevant association between nutritional variables and oral mucositis
severity.
RESULTS
During a 24-month period, 44 patients met the criterion for inclusion and signed an informed consent. Of
these, 4 patients were inevaluable: 1 patient never
returned to start treatment, 1 patient withdrew consent, and 2 patients were dropped within 2 weeks due
to absence of baseline or serial measurement data.
Forty patients were considered on an intent-to-treat basis. Table 2 summarizes baseline characteristics of
658
Nutrition Intake Related to Oral Mucositis
these 40 patients. Based on the TNM classification,
patients were put into American Joint Committee on
Cancer stage groups.16 Eighty-seven percent of patients
had TNM classification III or IV squamous cell carcinoma. Thirty-seven of the 40 patients (92.5%) completed at least 60 Gy of radiation delivered over 5 to 9
weeks. Induction chemotherapy was delivered to 21
patients (52.5%). Concurrent chemotherapy was administered to 33 patients (82.5%). Five patients (12.5%)
were treated with monotherapy regimens, including
cetuximab (4; 10%) or paclitaxel (1; 2.5%). Twenty-eight
patients were treated with high-dose cisplatin or polychemotherapy, with regimens of highest frequency
including: cisplatin-docetaxel-capecitabine (14; 35%),
carboplatin-paclitaxel (5; 12.5%), carboplatin-paclitaxel-cetuximab (3; 7.5%), and cisplatin (3; 7.5%). Two
patients (5.0%) were dependent on feeding tubes before
initial assessment by the radiation oncologist. Twentyseven patients (67.5%) had feeding tubes placed before
or during radiation treatment, including 5 patients who
required emergent placement. The median on-treatment weight loss for all patients was 5.6 kg (7.1% of
baseline weight). The 10 patients who met or exceeded
calorie goals had a median weight loss of 2.9 kg (or
4.1%). The median weight loss for all patients not meeting 100% of calorie goals was 6.2 kg (or 7.2%).
Oral mucositis was graded weekly for each patient
in accordance with CTCAE v. 3 criteria,20 with a median of 7 measurements for each individual. One
patient with tonsillar carcinoma developed no clinically measurable oral mucositis. Six patients (15%)
had a peak oral mucositis severity of grade 1; 13
patients (33%) had a peak oral mucositis severity of
grade 2, and 20 patients (50%) had a peak oral mucositis severity of grade 3. Patients with grade 3 oral
mucositis experienced a median of 2 weeks at that severity with a range of 1 to 6 weeks. No patient developed grade 4 oral mucositis.
An unadjusted proportional odds model was constructed for each nutritional goal. Table 3 presents
Table 3. Unadjusted odds of mucositis being less severe among
patients meeting calorie and protein goals relative to patients not
meeting goals.
Odds
ratio
Lower 95%
confidence
limit
Met goal current week
Calories
2.02
Protein
2.48
Calories and protein
1.70
Met goal previous week
Calories
1.57
Protein
2.74
Calories and protein
1.95
Met goal current and previous week
Calories
1.96
Protein
3.79
Calories and protein
2.52
Upper 95%
confidence
limit
p value
1.08
1.42
0.90
3.80
4.32
3.20
.03
.004
.11
0.79
1.57
0.97
3.14
4.78
3.92
.22
.004
.09
0.89
2.01
1.18
4.32
7.16
5.37
.11
.0001
.04
HEAD & NECK—DOI 10.1002/hed
May 2012
Table 4. Adjusted odds of mucositis being less severe among patients
meeting calorie and protein goals relative to patients not meeting goals.
Odds
ratio
Lower 95%
confidence
limit
Met goal current week
Calories
1.80
Protein
2.49
Calories and protein
1.49
Met goal previous week
Calories
1.15
Protein
2.78
Calories and protein
1.80
Met goal current and previous week
Calories
1.71
Protein
5.26
Calories and protein
3.38
Upper 95%
confidence
limit
p value
0.76
1.42
0.70
4.29
4.36
3.14
.18
.002
.30
0.48
1.50
0.80
2.78
5.15
4.08
.76
.001
.16
0.57
2.78
1.43
5.10
9.97
8.04
.34
< .0001
.006
unadjusted odds ratios (ORs) with 95% confidence
limits for the association between severity of oral
mucositis and individual nutritional goals. Reduction
in oral mucositis severity was statistically significantly associated (p < .05) with meeting 5 of 9 defined
nutritional goals. The association was strongest for
meeting the protein goal at 100% for the current and
prior week (OR, 3.79 for oral mucositis being less
severe; confidence interval [CI], 2.01–7.16).
Table 4 presents adjusted ORs with 95% CIs for the
association between individual nutritional goals and severity of oral mucositis, accounting for time on treatment and baseline characteristics. The odds of having
less severe oral mucositis were significantly associated
with the following nutritional goals: (1) meeting protein
goal for the current week (OR, 2.30; 95% CI, 1.32–
3.98); (2) meeting protein goal for the prior week (OR,
2.58; 95% CI, 1.36–4.89); (3) meeting protein goal for
current and prior week (OR, 4.72; 95% CI, 2.68–8.33);
and (4) meeting calorie and protein goals for current
and prior weeks (OR, 3.15; CI, 1.45–6.86). As with the
unadjusted analysis, oral mucositis severity was most
strongly associated with meeting the protein goal for
both the present week and prior week.
As many of the nutrition goals are strongly related, a
backward selection model was created to determine
more important nutritional predictors of oral mucositis
severity, starting from a proportional odds model that
included all 9 nutritional effects. Table 5 presents the
ORs from this multivariate analysis, adjusted for baseline characteristics and time on treatment. Baseline and
treatment characteristics significantly associated with
oral mucositis severity included anatomic site (p ¼ .009)
and week on treatment (p ¼ .001). The larynx site was
associated with reduced oral mucositis severity, whereas
the pharynx and lip/oral cavity sites were associated
with increased oral mucositis severity. Type of radiation
was not a significant predictor of oral mucositis severity.
Concurrent chemotherapy as categorized (none; monotherapy; polychemotherapy or high-dose cisplatin) did
not significantly predict oral mucositis severity. Patients
who received no concurrent chemotherapy did have
Nutrition Intake Related to Oral Mucositis
improved odds of less severe oral mucositis (adjusted OR
¼ 1.46) compared to the reference standard of polychemotherapy or high dose cisplatin; however, this association was not significant (p ¼ .17). After sequential
elimination of insignificant nutritional effects, meeting
the protein goal for the current week was the only statistically significant nutritional effect at the 5% level.
Patients who met the protein goal for the current week,
defined as the past 7 days, had significantly improved
odds of less severe oral mucositis (p ¼ .010, adjusted OR,
2.30; 95% CI, 1.32–3.98).
DISCUSSION
Oral mucositis is a nearly universal toxicity in
patients undergoing radiation for head and neck cancer. Even mild oral mucositis results in measurable
deterioration of quality of life.8,22 Clinical and economic consequences become more serious as oral
mucositis increases in severity. Severe oral mucositis
is associated with higher rates of hospitalization and
emergency room visits, opioid use, and non-oral nutritional and fluid supplementation. Severe oral mucositis leads to unplanned treatment interruptions in a
significant proportion of patients, ranging from 11% to
Table 5. ORs for less severe mucositis with 95% CI. Backward
selection model adjusting for week on treatment and baseline
characteristics.
Effect
Category
Meets protein goal
Site
TNM classification
Age
PG-SGA*
Induction
chemotherapy
Chemotherapy type
Radiation type
Current smoker
Current alcohol use
Baseline feeding
Week
Yes
No
Lip/oral cavity
Pharynx
Larynx
Nasal or salivary
II
III
V
Well nourished
Moderate
malnutrition
None
Yes
None
Single agent
Platinum or
2þ chemo
drugs
Intensity modulated
radiotherapy
Helical tomotherapy
No
Yes
No
Yes
Oral
Oral þ tube
Tube
OR (95% CI)
Effect
p value
2.30 (1.32–3.98)
1.00 (reference)
0.14 (0.03–0.60)
0.62 (0.13–2.98)
1.43 (0.33–6.27)
1.00 (reference)
2.89 (0.94–8.84)
1.33 (0.72–2.47)
1.00 (reference)
0.99 (0.95–1.034
0.59 (0.13–2.72)
1.00 (reference)
.01
2.27 (0.45–11.32)
.40
1.00 (reference)
1.46 (0.19–10.91)
0.15 (0.03–0.82)
1.00 (reference)
0.81 (0.33–1.98)
1.00 (reference)
0.59 (0.31–1.11)
1.00 (reference)
0.98 (0.41–2.34)
1.00 (reference)
0.88 (0.21–3.63)
0.40 (0.10–1.61)
1.00 (reference)
0.72 (0.61–0.84)
.009
.16
.69
.51
.17
.69
.07
.96
.10
.001
Abbreviations: OR, odds ratio; CI, confidence interval; PG-SGA, Patient GeneratedSubjective Global Assessment.17
HEAD & NECK—DOI 10.1002/hed
May 2012
659
19%, depending upon radiation fractionation schedule
and concurrent chemotherapy administration.23 Treatment breaks compromise oncologic efficacy and are
associated with a significant reduction in locoregional
control and overall survival.24 Given the clinical and
economic burdens of oral mucositis, strategies which
prevent or ameliorate this toxicity are sorely needed to
enhance quality of life and treatment efficacy. To date,
the only effective strategies in head and neck cancer
include good oral hygiene and application of modern
radiotherapy techniques that minimize exposure of normal tissue not involved with cancer.
Results from this study show that patients with
head and neck cancer who met nutritional goals during radiotherapy had significantly greater odds of less
severe oral mucositis than patients who did not meet
goals. After adjustment for time on treatment and
baseline characteristics, 4 nutritional variables incorporating a protein goal were significant predictors of
oral mucositis severity. An adjusted backward selection model indicated that current protein was a significant predictor of oral mucositis severity, even after
accounting for the well-described effects of site, TNM
classification, concurrent chemotherapy, and time on
treatment. These results suggest that the most important nutritional determinant of oral mucositis severity evaluated in this study is proximal protein intake,
that is, protein intake within the past 7 days meeting
the goal of 1.5 g/kg/day. The clinical implication of
this finding is simple: ongoing nutritional assessment
and counseling during radiation, with particular focus
on meeting protein-related nutritional goals, may
reduce oral mucositis severity.
Nutrition is an omnibus term encompassing the
biochemical constituents of food essential for all biological functions, including wound healing. The most
fundamental nutrients are energy, derived from carbohydrates and fat, and protein. Animal models have
demonstrated that gross protein depletion compromises wound healing.25 Human studies affirm that
surgical patients with protein-energy malnutrition exhibit impaired wound healing compared to well-nourished patients. This impairment occurs early in the
course of protein-energy malnutrition, when mild
malnourishment is detectable only by history of
reduced dietary intake and not by anthropometric
variables, such as weight or body mass index.14 The
most important nutritional variable in surgical wound
healing seems to be proximity of adequate dietary
intake, rather than the preexisting degree of proteinenergy malnutrition. Even anthropometrically malnourished patients undergoing elective gastrointestinal surgery demonstrate normal wound healing,
provided adequate food intake was in close proximity,
1 week, to the wound occurrence.15 Oral mucositis
has obvious pathobiologic differences from surgical
wound healing, particularly with regard to mechanism
and time span of injury and is no longer viewed as a
simple linear model of epithelial damage followed by
660
Nutrition Intake Related to Oral Mucositis
healing. A recent model describes 5 overlapping
phases: (1) initiation, with radiation-induced DNA
damage in submucosal endothelial cells; (2) upregulation and message generation, with activation of multiple pathways including ceramide-dependent apoptosis
and NF-jB modulation of proinflammatory cytokines;
(3) amplification of damage response pathways; (4)
ulceration, subsequent to loss of the epithelial trophic
factor, keratinocyte growth factor; and (5) healing.26
The healing phase is least understood, however, analogous to surgical wound healing, the cellular activities required for chronic tissue repair of mucous
membranes injured by daily radiation therapy fundamentally depend upon availability of energy and
amino acids. Although adequate nutrition alone
would be insufficient to prevent oral mucositis, current availability of essential nutrients for healing
may lessen the severity. The influence would be
expected to be more pronounced with protein intake,
because energy is a stored nutrient accessible during
deprivation, whereas protein is not.
Nutritional support has been previously associated with a reduction in oral mucositis severity in an
unplanned analysis of Radiation Therapy Oncology
Group 90-03. This randomized trial was designed to
evaluate 4 radiation fractionation schedules in
patients with locally advanced squamous cell carcinoma of the head and neck.27 Patients were retrospectively categorized into 3 nutritional groups: those
receiving oral, enteral, or parenteral nutritional support before the initiation of radiotherapy, those receiving nutritional support during treatment, and those
who received no nutritional support. Patients administered nutritional support before radiotherapy
trended toward less grade 3 and 4 oral mucositis,
compared to patients receiving on-treatment support
or no nutritional support, despite higher tumor and
nodal stage, which are associated with greater volume
of mucosal irradiation. Although a provocative association was noted between the patients who started
receiving nutrition support before treatment and
reduction in 5-year locoregional control and survival,
inferior outcome was not demonstrated in the group
of patients (59%) who received nutritional support
during treatment.
The results from our study are strengthened by
prospective design and data collection. Patients
received standard instructions on oral hygiene and
were instructed on strategies to reduce oral mucositis
symptom burden in accordance with international
guidelines.28 Intensive nutrition counseling was used
to help patients meet goals for calorie and protein
intake.29,30 Patients’ nutritional needs were assessed
according to a uniform calculation, accounting for
increased basal needs of a physiologically stressed
patient with cancer. Patients’ ongoing nutritional
intake was assessed weekly by use of a 24-hour food
recall, a labor-intensive methodology subject to significantly less measurement error than food frequency
HEAD & NECK—DOI 10.1002/hed
May 2012
questionnaires.31 Prospective, weekly measurements
improved accuracy and permitted analysis of temporal associations. Although oral mucositis studies can
be limited by non-uniform assessment and underreporting,8 here, patients had study-mandated weekly
grading by experienced radiation oncologists according to standardized national criteria.
This study has several important limitations. Rigorous data collection was limited by practical design to the
treatment period; long-term nutritional, functional, and
oncologic outcomes are unknown. All patients with head
and neck cancer undergoing 60 Gy of radiation were
eligible, thus there was considerable heterogeneity with
regard to anatomic site, TNM classification, and histology. In addition, patients were not treated with a
uniform chemoradiotherapy regimen. Chemotherapy
regimens were particularly heterogeneous, as they were
prescribed by multiple medical oncologists in 2 practice
settings. This likely impaired our ability to detect a significant association between concurrent chemotherapy
type and oral mucositis severity, although the reduced
severity among nonchemotherapy patients was in the
expected direction. Despite acknowledged heterogeneity,
the study had adequate power to detect a significant
association between nutritional endpoints and oral
mucositis severity. Moreover, adjustment for anatomic
site, TNM classification, time on treatment, concurrent
chemotherapy, and radiation type—all known to be associated with oral mucositis severity—did not dampen the
association.
Nutritional research is methodologically challenging
with regard to accurate measurement of nutrient intake,
which is largely reliant on 2 self-report methods: foodfrequency questionnaires and 24-hour recall. Our study
relied on repeat 24-hour recalls for macronutrient
assessment, a method with a 0.58 4-year validity estimate when conducted in the context of a dietary intervention trial.32 Results from large epidemiologic studies
among patients without cancer indicate that measurement of food intake on 7 to 14 nonconsecutive days reliably classifies individuals with regard to most nutrients,
including protein and calories, with only minor differences in weekday versus weekend consumption.33 However, similar studies of reliability have not been
conducted in patients with cancer on treatment, a critically different context in which treatment itself may alter intake. Whereas patient-reported dietary intake is
subject to both underreporting and over-reporting, we
did observe that patients who reported more calorie and
protein intake had less weight loss, evidence that
reported intakes were reliable. Assessing patients’ nutritional requirements is also controversial, as there are
different methods for calculating protein and energy
needs. Here, we applied a uniform calculation based
upon actual body weight at the beginning of radiation
treatment, regardless of the patient’s body mass index or
prior nutritional status. While we used a consistent
standard for estimating nutritional goals, it is unknown
whether alternate goals would have a differential impact
Nutrition Intake Related to Oral Mucositis
on oral mucositis severity, for example, increasing the
protein and calorie goals. Increasing protein may have a
detrimental effect on the kidneys, a particular concern
for patients receiving nephrotoxic chemotherapy.
A final limitation of our finding, that meeting protein-related nutritional goals is associated with less
severe oral mucositis during radiotherapy for head and
neck cancer, is certainly regarding the direction of the
association. We contend that meeting protein goals may
mitigate the severity of oral mucositis, based on principles extrapolated from surgical wound healing. A converse direction to this association is plausible, namely,
that oral mucositis causes nutritional compromise mediated by pain and dysphagia. In this regard, one would
expect a metric of global malnutrition, specifically calorie
intake, to associate significantly with oral mucositis severity. However, this is not the case for data presented
here. It is unlikely that oral mucositis caused selective
omission of protein from the diet. The repeated measurement structure of our data permits some temporal analysis of the association. Of note, the prediction of current
oral mucositis, based upon earlier oral mucositis severity,
was improved by accounting for whether subjects also
met protein goals on that date. However, predicting
whether subjects met current protein goals from past
protein goal performance was not improved statistically
by taking oral mucositis severity into account (data not
shown). Thus, in our study, current or previous oral
mucositis severity was not predictive of achieving protein goals. While not conclusive of causality, these findings support the possibility that optimal protein intake
attenuates the severity of mucositis.
Oral mucositis is a nearly universal consequence
of definitive treatment for head and neck cancer with
considerable negative impact on quality of life, health
care resource utilization, and therapeutic outcomes.
Despite increasing insight into the pathobiology of
oral mucositis, with identification of potential therapeutic targets for selective mucosal protection, no
drug has been shown to definitively lessen the severity or decrease the duration of oral mucositis in
patients with head and neck cancer undergoing radiotherapy.34,35 This study offers evidence that meeting
protein goals during radiation for head and neck
cancer is strongly associated with less severe oral
mucositis. Although a causal relationship cannot be
concluded from an associative study, from a practical
standpoint, protein intake is a manipulable variable,
which could be targeted for intervention. Optimizing
nutritional care during head and neck cancer radiation with specific guidelines for protein and calorie
intake is the inferred prevention strategy, and is feasible in most oncology clinics. This practical strategy
represents our current standard of care for patients
with head and neck cancer.
Results from the current study justify further
investigation of the relationship between nutritional
intake and oral mucositis. Future studies would be
strengthened by homogeneity with regard to TNM
HEAD & NECK—DOI 10.1002/hed
May 2012
661
classification, site, radiation fractionation schedule,
and chemotherapy regimen. Consideration should be
given to patient-centered symptom assessment,36 a
randomized design evaluating different macronutrient
prescriptions, and incorporation of a biochemical reference standard such as 24-hour urine nitrogen to validate patient-reported intake. Moreover, given adequate
protein intake predicts lesser severity of oral mucositis,
protein intake should be considered a potential
cofounder in future oral mucositis intervention studies.
Finally, a fundamental question raised by this study is
how protein intake may modulate the pathobiology of
oral mucositis. This question may be elucidated in follow-up nutrition intervention trials by correlative studies, such as serial measurement of proinflammatory
cytokines, which mediate mucosal injury including constituents of the tumor necrosis factor alpha, nuclear
factor-kappa B, and cyclooxygenase 2 pathways. Rigorous testing of causal relationships between nutritional
variables and oral mucositis severity could be conducted in available murine models.
REFERENCES
1. SEER Stat Fact Sheets 6/2009. http://seer.cancer.gov/statfacts/
html/oralcav.html;
http://seer.cancer.gov/statfacts/html/laryn/
html; http://seer.cancer.gov/statfacts/html/tongue.html.
2. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous
cell head and neck cancer. J Clin Oncol 2003;21:92–98.
3. Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or
accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368:843–854.
4. Vera–Llonch M, Oster G, Hagiwara M, Sonis S. Oral mucositis
in patients undergoing radiation treatment for head and neck
carcinoma. Cancer 2005;106:329–336.
5. Palazzi M, Tomatis S, Orlandi E, et al. Effects of treatment
intensification on acute local toxicity during radiotherapy for
head and neck cancer: prospective observational study validating
CTCAE, version 3.0, scoring system. Int J Radiat Oncol Biol
Phys 2008;70:330–337.
6. Elting LS, Cooksley CD, Chambers MS, Garden AS. Risk, outcomes, and costs of radiation-induced oral mucositis among
patients with head-and-neck malignancies. Int J Radiat Oncol
Biol Phys 2007;68:1110–1120.
7. Bruner DW, Hass ML, Gosselin–Acomb TK, editors. Manual for
radiation oncology nursing practice and education. 3rd ed. Pittsburgh: ONS: 2005, pp 86–97.
8. Murphy BA. Clinical and economic consequences of mucositis
induced by chemotherapy and/or radiation therapy. J Support
Oncol 2007;5(9 Suppl 4):13–21.
9. Russo G, Haddad R, Posner M, Machtay M. Radiation treatment
breaks and ulcerative mucositis in head and neck cancer. Oncologist 2008;13:886–898.
10. Rosenthal DI. Consequences of mucositis-induced treatment
breaks and dose reductions on head and neck cancer treatment
outcomes. J Support Oncol 2007;5(9 Suppl 4):23–31.
11. Bese NS, Hendry J, Jeremic B. Effects of prolongation of overall
treatment time due to unplanned interruptions during radiotherapy of different tumor sites and practical methods for compensation. Int J Radiat Oncol Biol Phys 2007;68:654–661.
12. Mahan K, Escott–Stump S, editors. Krause’s Food Nutrition and
Diet Therapy. Philadelphia: W.B. Saunders, 2000.
13. Williams SR. Nutrition and Diet Therapy. St. Louis: Mosby, 1997.
14. Haydock DA, Hill GL. Impaired wound healing in surgical
patients with varying degrees of malnutrition. JPEN J Parenter
Enteral Nutr 1986;10:550–554.
662
Nutrition Intake Related to Oral Mucositis
15. Windsor JA, Knight GS, Hill GL. Wound healing response in
surgical patients: recent food intake is more important than
nutritional status. Br J Surg 1988;75:135–137.
16. Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer
Staging Manual (ed 6), Chicago, IL, American Joint Committee
on Cancer 2002.
17. Isenring E, Bauer J, Capra S. The scored Patient-generated Subjective Global Assessment (PG-SGA) and its association with
quality of life in ambulatory patients receiving radiotherapy.
Eur J Clin Nutr 2003;57:305–309.
18. Hurst JD, Gallagher AL. Energy, macronutrient, micronutrient,
and fluid requirements. In: Elliott L, Molseed LL, McCallum
PD, editors. The Clinical Guide to Oncology Nutrition. American
Dietetic Association, 2006, p 56.
19. Eliers J. Nursing interventions and supportive care for the prevention and treatment of oral mucositis associated with cancer
treatment. Oncol Nurs Forum 2004;31(4 Suppl):13–23.
20. Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0- June 10, 2003, National Institutes of Health, National
Cancer Institute, pp 21, 24.
21. Rochon J. Application of GEE procedures for sample size calculations
in repeated measures experiments. Stat Med 1998;17: 1643–1658.
22. Elting LS, Deefe DM, Sonis ST, et al. Patient-reported measurements of oral mucositis in head and neck cancer patients treated
with radiotherapy with or without chemotherapy: demonstration
of increased frequency, severity, resistance to palliation, and
impact on quality of life. Cancer 2008;113:2704–2713.
23. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence,
severity and associated outcomes in patients with head and
neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 2003;66:
253–262.
24. Pajak TF, Laramore GE, Marcial VA, et al. Elapsed treatment
days—a critical item for radiotherapy quality control review in
head and neck trials: RTOG report. Int J Radiat Oncol Biol
Phys 1991;20:13–20.
25. Daly JM, Vars HM, Dudrick SJ. Effects of protein depletion on
strength of colonic anastomosis. Surg Gynecol Obstet 1972;134: 15–21.
26. Sonis ST. Pathobiology of oral mucositis: novel insights and
opportunities. J Support Oncol 2007;5(9 Suppl 4):3–11.
27. Rabinovitch R, Grant B, Berkey BA, et al. Impact of nutrition
support on treatment outcome in patients with locally advanced
head and neck squamous cell cancer treated with definitive
radiotherapy: a secondary analysis of RTOG trial 90–03. Head
Neck 2006;28:287–296.
28. Rubenstein EB, Peterson DE, Schubert M, et al. Clinical practice
guidelines for the prevention and treatment of cancer therapyinduced oral and gastrointestinal mucositis. Cancer 2004;100(9
Suppl):2026–2046.
29. Isenring E, Capra S, Bauer JD. Nutrition intervention is
beneficial in oncology outpatients receiving radiotherapy to the
gastrointestinal or head and neck area. Br J Cancer 2004;
91:447–452.
30. Ravasco P, Monteiro–Grillo I, Vidal PM, Camilo ME. Dietary
counseling improves patient outcomes: a prospective, randomized controlled trial in colorectal cancer patients undergoing
radiotherapy. J Clin Oncol 2005;23:1431–1438.
31. Schatzkin A, Subar AF, Moore S, et al. Observational epidemiologic studies of nutrition and cancer: the next generation. Cancer Epidemiol Biomarkers Prev 2009;18:1026–1032.
32. Natarajan L, Pu M, Fan J, et al. Measurement error of dietary
self-report in intervention trials. Am J Epidemiol 2010;172:819–
827.
33. Hartman AM, Brown CC, Palmgren J, et al. Variability in nutrient and food intakes among older middle-aged men: implications
for design of epidemiologic and validation studies using food
recording. Am J Epidemiol 1990;132:999–1012.
34. Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis
in patients who have cancer. Dent Clin North Am 2008;52:61–
77.
35. Posner MR, Haddad RI. Novel agents for the treatment of mucositis. J Support Oncol 2007;5(9 Suppl 4):33–39.
36. Elting LS, Keefe DM, Sonis ST, et al. Patient-reported measurements of oral mucositis in head and neck cancer patients treated
with radiotherapy with or without chemotherapy: demonstration
of increased frequency, severity, resistance to palliation, and
impact on quality of life. Cancer 2008;113:2704–2713.
HEAD & NECK—DOI 10.1002/hed
May 2012