Download impact of nutrition support on treatment outcome in

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
Rachel Rabinovitch, MD,1 Barbara Grant, MS, RD,2 Brian A. Berkey, PhD,3 David Raben, MD,2
Kie Kian Ang, MD,4 Karen K. Fu, MD,5 Jay S. Cooper, MD6 for the Radiation Therapy
Oncology Group
1
Department of Radiation Oncology, University of Colorado Health Sciences Center,
Anschutz Cancer Pavilion, 1665 N. Ursula Street, Suite 1032, Box F706, Aurora, CO 80045.
E-mail: [email protected]
2
Cancer Care Center, Saint Alphonsus Regional Medical Center, Boise, Idaho
3
RTOG Headquarters, Philadelphia, Pennsylvania
4
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center,
Houston, Texas
5
Department of Radiation Oncology, University of California San Francisco, San Francisco, California
6
Department of Radiation Oncology, Maimonides Medical Center, Brooklyn, New York
Accepted 1 August 2005
Published online 14 November 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20335
Abstract: Background. The aim was to evaluate the relationship between nutrition support (NS) on host toxicity and cancer
outcome in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing definitive radiotherapy (XRT).
Methods. We performed a secondary analysis of Radiation
Therapy Oncology Group (RTOG) 90-03, a prospective randomized trial evaluating four definitive XRT fractionation schedules in
patients with locally advanced HNSCC, which prospectively collected data on NS delivered before treatment (BNS), during
treatment (TNS), and after definitive XRT. NS data and pretreat-
Correspondence to: R. Rabinovitch
Presented at the annual meeting of the American Society for Therapeutic Radiology and Oncology, 2002.
C
V
2005 Wiley Periodicals, Inc.
Impact of Nutrition Support
ment characteristics of the 1073 evaluable patients were analyzed against therapy toxicity and outcome.
Results. Patients receiving BNS experienced significantly
less weight loss by the end of treatment and less grade 3 to 4
mucositis than patients not receiving BNS. However, patients
receiving BNS had a poorer 5-year actuarial locoregional control
rate than patients receiving TNS or no NS (29%, 55%, and 57%,
respectively, p < .0001) and a poorer 5-year overall survival rate
(16%, 36%, and 49%, respectively, p < .0001). Patients receiving BNS were significantly more likely to have a higher T classification, N status, and overall American Joint Committee on Cancer (AJCC) stage and initial presentation with greater pretreatment weight loss, and a poorer Karnofsky Performance Status
(KPS) than patients not receiving BNS. After adjusting for the
impact of these prognostic factors through a recursive partition
analysis, a multivariate analysis with a stratified Cox model found
that BNS was still a highly significant independent prognostic
factor for increased locoregional failure (hazards ratio [HR],
HEAD & NECK—DOI 10.1002/hed
April 2006
287
1.47; 95% confidence interval [CI], 1.21–1.79; p < .0001) and
death (HR, 1.41; 95% CI, 1.19–1.67; p < .0001).
Conclusion. In this study, the largest prospective evaluation
of nutrition data in treated patients with cancer, BNS was associated with inferior treatment outcome in the patients with HNSCC
undergoing XRT. These results should be considered hypothesis
generating and encourage prospective clinical research and
C 2005
identification of the mechanisms underlying this finding. V
Wiley Periodicals, Inc. Head Neck 28: 287–296, 2006
Keywords: nutrition; radiotherapy; outcome; cancer; head and
neck
Malignancies
of the head and neck frequently
result in diminished nutritional intake because of
local symptoms (painful and impaired chewing
and swallowing) caused by physical invasion of
regional structures. Head and neck cancers, similar to many other malignancies, may also induce
constitutional symptoms (decreased appetite and
cachexia), further negatively impacting on nutritional intake and maintenance of body mass. Specific to this population, patients with head and
neck cancer commonly present with preexisting
nutritional deficiencies because of poor lifetime
personal habits, such as excessive alcohol consumption, tobacco use, and longstanding inadequate nutritional intake and a greater incidence
of anemia.1,2
It is, therefore, a significant challenge to maintain the nutritional status of the patient with head
and neck cancer throughout a definitive course of
head and neck radiotherapy, given the profound
acute impact of radiation on oropharyngeal mucosa. For all of these reasons, patients undergoing
definitive head and neck radiotherapy frequently
require alternate methods of nutrition support
(NS), administered through various combinations
of oral, enteral (via tube), and parenteral routes.
Depending on the severity of pretreatment swallowing function, pain, and treatment-induced mucositis, NS may partially or completely replace normal oral nutritional intake.
There is ample information that NS enhances
host outcomes (ie, improves the cancer patient’s
subjective quality of life) and improves or stabilizes patient body mass.3–6 Although many patients
and clinicians express the notion that nutritional
support may be beneficial in ‘‘fighting the cancer,’’
the limited data available from small groups of
treated animals and human patients actually suggest that NS has a negative association with cancer outcomes (ie, increased tumor growth and decreased effectiveness of cancer therapy).7 There
are little clinical data in humans evaluating the
association of NS or other specific nutritional pa-
288
Impact of Nutrition Support
rameters with host outcomes (acute and late toxicity) in a uniformly treated population of patients
with cancer; there are also little data on the potential relationship of NS on cancer therapy outcome
in such patients.
This study, an unplanned re-analysis of the
Radiation Therapy Oncology Group (RTOG) protocol 90-03 was performed to evaluate for an association of NS with host toxicity and cancer outcomes
in patients treated with definitive radiotherapy
for locally advanced head and neck squamous cell
carcinoma (HNSCC). RTOG 90-03, a definitive
radiotherapy treatment trial for patients with
HNSCC, prospectively collected data on NS for
patients at baseline (BNS), during treatment
(TNS), and throughout follow-up. Issues related
to this nutrition data have not been previously
analyzed. This analysis constitutes the largest
evaluation of prospectively collected NS data and
its effect on treatment outcome in patients with
cancer participating in a clinical cooperative group
trial.
MATERIALS AND METHODS
RTOG 90-03 was a phase III prospective randomized trial designed to compare four definitive
radiotherapy fractionation schedules for patients
with locally advanced HNSCC: standard fractionation, twice daily hyperfractionation (HFX), accel
erated fractionation with a split (AFX-S), and
accelerated fractionation with a concomitant boost
(AFX-C). The primary objectives of this trial were
to (1) test the efficacy of hyperfractionation and
two types of accelerated fractionation against
standard fractionation with regard to locoregional
control, and (2) compare acute and late toxicities
between the different fractionation regimens.
Between 1991 and 1997, 1113 patients were enrolled, and 1073 of these patients were analyzed
for outcome. Neck dissection was allowed only for
neck nodes >3 cm before radiation therapy, and
patients did not receive chemotherapy during initial treatment. The overall details and results of
this trial were published in 2000.8
This analysis examined pretreatment patient
and tumor characteristics; type of NS used before, during, and after radiation therapy; incidence and severity of acute and late toxicities;
elapsed days of treatment; and ultimate treatment outcome (Table 1). NS information was
documented in the protocol’s data capture forms
as follows: (1) oral liquid nutritional supplements,
(2) enteral nutrition by means of a feeding tube,
HEAD & NECK—DOI 10.1002/hed
April 2006
Table 1. Variables analyzed.
o
o
o
o
o
o
o
o
o
Primary tumor site
T classification, N classification, and AJCC stage
Age
Sex
KPS
Assigned protocol treatment
Dysphagia at baseline (pretreatment)
Mucositis at treatment completion
Specific nutrition support (oral liquid nutrition supplements,
enteral nutrition via feeding tube, or parenteral nutrition)
n Baseline (before treatment initiation)
n Completion of treatment
n 3 mo after treatment
n 6 mo after treatment
o Pretreatment Hgb
o Weight loss
n 6 mo before treatment
n At completion of treatment
o Treatment outcomes
n Incidence of treatment breaks
n Elapsed days of treatment
n Local regional control
n Overall survival
Abbreviations: AJCC, American Joint Committee for Cancer; KPS,
Karnofsky Performance Status; Hgb, hemoglobin.
and/or (3) parenteral nutrition. Of note, RTOG
90-03 did not mandate any guidelines for NS initiation or content.
The distribution of patient and treatment
characteristics for various patient subgroups was
compared by the Pearson chi-square test for discrete data and the Wilcoxon test for continuous
data. Locoregional control was estimated by the
method of cumulative incidence,9 and statistical
testing was performed with Gray’s test.10 Overall
survival (OS) was estimated by the Kaplan-Meier
method,11 and statistical testing was performed
with the log-rank test.12
A recursive partitioning analysis (RPA) was
performed to identify subgroups of patients that
had distinct results with respect to survival and
locoregional control using pretreatment prognostic factors for patients with HNSCC (age, sex,
weight loss before start of treatment, hemoglobin,
T classification, N status, overall American Joint
Committee on Cancer [AJCC] stage, Karnofsky
Performance Status [KPS], primary site, and
baseline dysphagia). The RTOG previously used
RPA methodology to classify patients with head
and neck cancer.13 The analysis involves dichotomizing the patients using all logical splits of variables and finding the most significant difference
between the two groups (adjusting the level of
significance for the multiple comparisons). The
Impact of Nutrition Support
process is repeated within each subgroup until all
significant splits have been found and a set of
prognostic classes has been determined. Within
each final prognostic class, a univariate comparison was performed to assess for the impact of 6
BNS on locoregional failure and death from any
cause. The Cox proportional hazards model14 was
used for testing of 6 BNS on both locoregional
failure and death in the entire set of patients
stratified by the RPA prognostic classes.
RESULTS
Pretreatment characteristics of the 1073 evaluable patients are shown in Table 2. Patients were
generally men, middle-aged, and had stage III or
IV HNSCC; the oropharynx was the most common primary site.
Before the initiation of radiation therapy, 27%
of all patients (n ¼ 293) were receiving BNS,
evenly distributed among protocol treatment
arms. Of the patients receiving BNS, 50% used
only oral liquid NS, 27% used only enteral nutrition by a feeding tube, 16% used a combination of
oral and enteral supplementation, and 6% used
parenteral support. Most patients (86%) required
some form of TNS, with an even distribution
among the treatment arms.
Patients receiving BNS were significantly
more likely to have a poorer KPS, higher primary
tumor (T) classification, more extensive regional
lymph node involvement (N status), greater overall AJCC stage, and a greater incidence of anemia
Table 2. Pretreatment characteristics.
Characteristic
Sex
Male
Female
Age, y
Median
Range
AJCC stage
II
III
IV
Dysphagia
None
Mild
Moderate
Severe
Unknown
Result
79%
21%
61
30–90
4% (base of tongue
and hypopharynx)
28%
68%
39%
23%
30%
8%
<1%
Abbreviation: AJCC, American Joint Committee on Cancer.
HEAD & NECK—DOI 10.1002/hed
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289
Table 3. Association between BNS and pretreatment
characteristics.
Pretreatment
characteristic
KPS
90–100
60–80
T classification
T1–2
T3–4
N classification
NO
Nþ
AJCC stage
II–III
IV
Dysphagia at baseline
None/mild
Moderate/severe
Hgb
Normal
Anemia*
Assigned treatment
Standard
HFX
AFX-S
AFX-C
% of patients by
BNS status
BNS
þBNS
p value
71
29
35
65
<.001
40
60
14
86
<.001
24
76
17
83
<.017
37
63
17
83
<.001
72
28
34
66
<.001
47
53
75
25
<.0001
25
24
25
26
24
25
28
23
.72
Abbreviations: BNS, baseline nutrition support; KPS, Karnofsky Performance Status; AJCC, American Joint Committee on Cancer; Hgb, hemoglobin; HFX, hyperfractionation; AFX-S, accelerated fractionation with a
split; AFX-C, accelerated fractionation with a concomitant boost.
*Anemia defined as <14.5 g% in men, and <13.0 g% in women.
compared with patients who did not (Table 3).
Patients receiving BNS had significantly greater
weight loss in the 6 months preceding treatment
(means of 7.8 kg vs 3 kg) than patients receiving
no BNS (p < .0001). Patients presenting with
grade 3 or 4 dysphagia before treatment initiation were significantly more likely to receive BNS
(p < .0001) and TNS (p < .015) than those with
grade 1 or 2 dysphagia, an observation consistent
between treatment arms.
By the completion of treatment, patients who
received BNS had significantly less weight loss
(median of 5% vs 7%,p< .0001) than those who
did not. There was a trend (p ¼ .057) toward a
lower incidence of grade 3 or 4 mucositis after
treatment in patients who received BNS (100 of
293; 34%) compared with those who did not (311
of 780; 40%).
At the time of this analysis (median follow-up,
64.2 months), there had been 553 local or regional
failures and 757 deaths reported among the
evaluable patients. As measured by univariate
analysis, patients receiving BNS, TNS, and no
290
Impact of Nutrition Support
NS had 5-year actuarial locoregional control rates
of 29%, 55%, and 57%, respectively (Figure 1). The
locoregional control rate for patients who received
BNS was significantly less than for patients who
received TNS and those receiving no NS, a consistent finding regardless of whether data were
analyzed for all patients in the study (Figure 1)
or by individual treatment arm (data not shown).
Similarly, there was no significant difference in
locoregional control rates between patients receiving no NS and patients receiving TNS, either in
the entire cohort of patients or within each treatment arm.
Univariate analysis also demonstrated that
patients receiving BNS had significantly poorer
5-year actuarial OS compared with patients receiving TNS or no NS (16%, 36%, and 49%, respectively; p < .0001) (Figure 2). This significantly
poorer OS rate for patients who received BNS was
observed within each treatment arm (data not
shown). OS for patients receiving TNS was significantly inferior to patients receiving no NS in
only one of the treatment arms: accelerated fractionation with split (p ¼ .046).
Patients receiving BNS were no less likely to
receive their total prescribed radiation dose than
other patients, means of 71.5 Gy vs 72.6 Gy, respectively (p ¼ .14). Patients receiving BNS also
completed their treatment within the same time
frame as other patients: means of 46.9 days versus 46.7 days, respectively (p ¼ .69).
The results of the RPA analyses for locoregional control and OS can be seen in Figures 3
FIGURE 1. Actuarial locoregional control by level of nutrition
support (all patients). Patients who received baseline nutrition
support before treatment initiation (BNS) had significantly inferior locoregional control compared with patients receiving nutrition support during treatment only (TNS) or no nutrition support
at baseline or during treatment (NS).
HEAD & NECK—DOI 10.1002/hed
April 2006
FIGURE 2. Actuarial overall survival (OS) by level of nutrition
support (all patients). Patients who received baseline nutrition
support before treatment initiation (BNS) had significantly inferior OS compared with patients receiving nutrition support during treatment only (TNS) or no nutrition support at baseline or
during treatment (NS).
and 4, respectively. The tree for locoregional control endpoint has nine prognostic classes with
sample sizes ranging from 10 to 428; the tree for
the OS endpoint yielded six prognostic classes
with sample sizes ranging from 62 to 497. Tables 4
and 5 show hazard rates for locoregional failure
and death, respectively, comparing the patients
who did and did not receive BNS within each of
the RPA-derived prognostic classes.With the exception of one class in which the ratio was equal
to 1, all of the hazard ratios are greater than 1,
indicating that in each class patients who received BNS had an increased risk of failure, al-
though the effect did not achieve significance,
likely because of small sample sizes. The Cox proportional hazards model was then used to evaluate the impact of BNS after stratifying for derived
prognostic classes of each endpoint. BNS was
found to be highly significant for an increased
risk of locoregional failure (hazard ratio [HR],
1.47; 95% confidence interval [CI], 1.21–1.79; p <
.0001) and death (HR, 1.41; 95% CI, 1.19–1.67;
p < .0001).
An analysis of treatment outcome taking into
account each of the routes of BNS administration
(ie, oral, enteral, and parenteral) was performed
using a Cox model stratified by the derived prognostic classes in the RPA. These results (Table 6)
continue to demonstrate significantly higher risks
of locoregional failure and death for each of the
routes of BNS (p ¼ .0033 and .0047, respectively).
It should be noted that the effects of oral and
enteral nutrition were similar to one another for
each outcome, whereas the parenteral effect was
larger.
DISCUSSION
The recognized goals of nutritional intervention
in the patient with cancer are to reverse or reduce
nutritional deficiencies,15 preserve lean body
mass, aid in recovery and healing,16,17 and maximize quality of life (QOL).18 These ‘‘host’’ benefits
of nutritional support for the patient with cancer
(ie, benefits to the patient’s own body and QOL)
FIGURE 3. Recursive partition analysis (RPA) derived tree of locoregional control.
Impact of Nutrition Support
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291
FIGURE 4. Recursive partition analysis (RPA) derived tree of overall survival.
are established in the literature.6,19–21 Klein
et al22 reviewed 28 prospective randomized trials
of F TPN in patients with cancer and reported
pooled reduction in postoperative complications
(p ¼ .01) and postoperative mortality (p ¼ .02) for
patients receiving TPN. Consistent with these
Table 4. Effect of baseline nutrition support on locoregional
failure within each RPA class and in all patients.
Class
1
2
3
4
5
6
7
8
9
All
BNS
status
No. of
patients
No. of
events
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
12
43
63
120
6
21
40
388
13
43
28
50
9
1
88
48
32
59
291
773
6
14
41
68
5
13
22
130
9
20
18
20
8
1
75
39
22
37
206
342
HR (95% Cl)
1.43 (0.55–3.72)
Impact of Nutrition Support
Table 5. Effect of baseline nutrition support on death within
each RPA class and in all patients.
1.36 (0.92–2.02)
1.25 (0.44–3.55)
1.98 (1.26–3.12)
Class
1
1.96 (0.87–4.38)
2
1.82 (0.96–3.44)
3
–
4
1.34 (0.90–1.99)
5
1.16 (0.68–1.98)
6
1.47 (1.21–1. 79)*
p < .0001
Abbreviations: RPA, recursive partitioning analysis; BNS, baseline nutrition support; HR, hazard rate; Cl, confidence interval.
The HR is > 1 in all classes analyzed, demonstrating an increased risk
of local failure for patients using BNS. There is a significant increased
HR for locoregional failure associated with BNS in all patients, stratified
for known prognostic variables.
*From a model stratified by the derived prognostic classes.
292
benefits of NS, patients who received BNS in this
RTOG study reaped host benefits as well: less
weight loss by treatment completion and a lower
incidence of grade 3 to 4 mucositis after the conclusion of therapy. One can further infer that the
addition of BNS allowed these patients to complete therapy in an identical time frame as
patients not receiving NS, despite their poorer
KPS and greater tumor burden.
A commonly held presumption exists that as a
result of the documented host benefits derived by
All
BNS
status
No. of
patients
No. of
events
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
BNSþ
BNS
24
79
166
145
16
81
41
359
32
58
12
50
291
772
21
56
149
121
13
56
29
184
25
44
12
41
249
502
HR (95% Cl)
1.43 (0.87–2.37)
132 (1.03–1.68)
1.27 (0.69–2.32)
1.82 (1.23–2.70)
1.00 (0.61–1.63)
3.02 (1.56–5.85)
1.41 (1.19–1.67)*
p < .0001
Abbreviations: RPA, recursive partitioning analysis; BNS, baseline nutrition support; HR, hazard rate; Cl, confidence interval.
The HR is > 1 in all but class 5. There is a significant increased HR for
death associated with BNS in all patients, stratified for known prognostic variables.
*From a model stratified by the derived prognostic classes.
HEAD & NECK—DOI 10.1002/hed
April 2006
Table 6. Effect of route of BNS administration locoregional
failure and death (each stratified by derived
prognostic classes).
Route of BNS
Locoregional failure
None
Oral
Enteral
Parenteral
Death
None
Oral
Enteral
Parenteral
HR (95% Cl)
p value
—
1.21 (0.97–1.50)
1.30 (1.01–1.66)
2.40 (1.36–4.21)
.0033
—
1.27 (1.05–1.52)
1.22 (0.98–1.53)
1.75 (1.07–2.87)
.0047
Abbreviations: BNS, baseline nutrition support; HR, hazards rate; Cl,
confidence interval.
the patient with cancer from NS, a consequent
negative impact on the malignancy should result.
Patients commonly express this belief— that good
nutrition support is important to ‘‘help my body
fight the cancer.’’ Preclinical and clinical data,
however, suggest just the opposite. That is,
whereas NS and appropriate dietary intake benefit the host by preserving body mass, minimizing
toxicity to therapy, and improving QOL, NS seems
to similarly benefit the malignancy as well.7
Although the cancer clinician may be surprised
by this concept, there is a growing body of literature, reported primarily in nutrition journals—
and hence largely unseen by most clinical oncologists—describing the tumor-enhancing effects of
NS in both animals and humans. Researchers experienced in feeding and ‘‘treating’’ tumor-bearing
rodents are familiar with this relationship. As
early as 1909, Moreschi23 documented that tumors
transplanted into mice fed ‘‘ad libitum’’ (as much
as desired) grew better than tumors transplanted
into underfed mice. The literature contains several
descriptions of diet restriction inhibiting tumor
growth in tumor-bearing animals.24,25 Conversely,
evidence exists that total parenteral nutrition
(TPN) delivery to tumor-bearing animals increases
tumor mass26–28 and stimulates a host of markers
indicative of tumor cell growth.29The stimulatory
effect of TPN on tumor growth parameters is recognized in rodent research, and recent work has
focused on manipulating specific dietary components to counteract this phenomenon.30–32 Ye
et al,30 Millis et al,31 and He et al32 have all independently compared various nutrition formulations and found that manipulation of specific
amino acid concentrations—focusing on arginine
and methionine balance—inhibited tumor growth
Impact of Nutrition Support
in tumor-bearing rodents. Interestingly, controversy exists in the literature as to whether TPN
stimulates tumor growth in the animal model to a
greater degree than oral dietary intake.28,33
In humans, epidemiologic data consistently
demonstrate an association between obesity and
an increased incidence of numerous cancers (breast,
uterus, esophagus, liver, prostate, gallbladder, larynx, kidney, cervix, ovary, brain, colon, and lymphoma).34–36 This observation indirectly refutes
the notion that well-fed individuals have better
immune or other mechanisms to prevent cancer
induction or cancer growth.
Clinical data directly evaluating the impact of
NS in cancer-bearing humans has involved small
patient numbers and frequently non-uniformly
staged or treated patients. Nevertheless, the available information also is consistent with the rodent
model described previously.
A retrospective analysis of the protein and
energy intake of 37 patients with metastatic melanoma or renal cell cancer showed a 50% reduction
in complete and partial responses to high-dose
interleukin-2 therapy among patients receiving
14 days of concurrent parenteral nutrition compared with controls with oral intake only.37 Overall survival was shown to be unchanged between
the two groups; however, time to progression of
disease was decreased, and tumors progressed
17% faster in patients receiving parenteral nutrition.
Baron et al38 evaluated tumor samples obtained
from 14 untreated patients with HNSCC before
and after TPN administration and compared them
with normal tissue samples from the same patients.
They identified a significant increase in the percentage of hyperdiploid cells in tumors after TPN
delivery, but no such changes were observed in
normal mucosa. Bozzetti et al39 evaluated the impact of preoperative TPN versus none in 19 malnourished patients with gastric cancer. Increased
3
H-thymidine labeling index, a marker for S-phase
cell fraction or tumor cell proliferation, was identified in half of the endoscopically biopsied tumor
specimens.
One of the largest prospective trials published
to date randomized 92 patients with operable gastrointestinal cancer (gastric, colon, and rectal
tumors) and malnutrition to one of four interventions before definitive surgery: parenteral NS,
parenteral NS and chemotherapy, chemotherapy,
or nothing (control).40 Parenteral NS resulted in a
significant stimulation of tumor proliferation as
measured by an increase of the percent of tumor
cells in S phase, DNA content, and DNA index.
HEAD & NECK—DOI 10.1002/hed
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293
Overall, clinical outcomes with regard to tumor
control and survival were not evaluated.
Although there is a clinical trial in small cell
lung cancer that did not identify a negative effect
of intravenous hyperalimentation on cancer therapy outcome,41 it is important to note that there
is no published documentation supporting the
idea that delivery of unmanipulated diets/NS to
humans or animals enhances tumor control or
improves cancer therapy outcome.
Our analysis of the 1073 patients treated and
evaluable on RTOG 90-03 comprises the largest
evaluation of NS on cancer treatment outcome in
a uniformly staged and treated group of patients
with cancer, albeit in an originally unplanned
analysis. The significant and large negative association of BNS on both locoregional control and
OS described here is striking and lends considerable weight to the repeated observation that NS
is associated not only with improved patient outcomes but inferior cancer outcomes as well.
The magnitude of the negative effect of BNS
on treatment outcome in the initial univariate
analysis of this report is impressive: patients who
received BNS had a 28% absolute reduction in
locoregional control compared with patients not
using any NS (29% vs 57% at 5 years), a relative
decrease of 49%. Similarly, the absolute difference in OS rate for patients receiving BNS compared with those never using NS was 33% (16%
vs 49% at 5 years), a relative decrease of 67%.
Because these observations may have important clinical implications, we made a concerted
effort to determine that the negative association
observed was indeed related to the BNS and not
the severe imbalance of the poorer prognostic features observed in those patients who received
BNS (advanced T classification, N status, and
AJCC stage, poor KPS, undesirable primary tumor site, and greater pretreatment weight loss).
To account for them, an RPA was performed identifying discrete classes of patients, which took
into account each of the poor prognostic factors
on locoregional control and OS. (RPA is a statistical tool used to determine the association of prognostic variables with a specific outcome). Only
then was BNS evaluated within each individual
prognostic class for its impact on locoregional failure and death, allowing us to isolate any effect of
BNS from the other prognostic factors already
taken into consideration. Hazard rates greater
than 1 (indicating a higher risk of failures) were
seen in all but one class for both locoregional failure and death (Tables 4 and 5). Evaluation for an
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Impact of Nutrition Support
association of BNS on the entire group of evaluable patients, stratified for the various RPA prognostic classes, was highly significant (p < .0001),
demonstrating a 47% increased risk of locoregional failure and a 41% increased risk of death
in patients receiving BNS. This method of analysis, in our opinion, is sufficiently rigorous to account for the differences in the prognostic profiles
of the patients who did and did not receive BNS.
We, therefore, believe that these data confirm an
association between use of BNS and greater
locoregional failure and death in the patients
evaluated on this study. This negative association
is consistent with the direct and indirect evidence
summarized earlier, supporting the theory that
NS has a negative impact on cancer therapy outcome.
The findings of this report raise many questions. What are the physiologic, cellular, and molecular mechanisms for decreasing the effectiveness of radiotherapy when patients receive BNS?
How is the patient who receives BNS nutritionally
different than someone who does not require supplementation? Will our observation be validated in
the setting of other malignancies and with other
anticancer modalities? How can the negative association of BNS on treatment outcome be mitigated
by either altering the composition of the BNS or
by introducing other interventions?
We acknowledge that an analysis of NS and
cancer outcome was not designated as an up-front
endpoint in this study, and the collected information regarding BNS is quite limited (ie, no data
captured on duration of support, nutritional content of support). However, the sheer magnitude
and statistical significance of the negative impact
of BNS identified on multivariate analysis (47%
increased risk of locoregional failure and 41% increased risk of death, both p < .0001) after
accounting for other associated negative prognostic factors through creation of RPA trees, lends
weight to the credence of these data. The value of
retrospective analyses is precisely that which
was achieved here, to mark effects and interactions not initially considered in the study design.
At a minimum, our data are hypothesis generating and justify a prospective analysis.
Evaluating BNS prospectively, the logical next
step, will, however, present substantial challenges.
BNS is often independently initiated by the patient
with cancer before evaluation by an oncologist,
preventing participation in a clinical trial evaluating this parameter de novo. The ethics of randomizing a nutritionally compromised patient with
HEAD & NECK—DOI 10.1002/hed
April 2006
cancer to 6 BNS will need thoughtful discussion.
(The RTOG is currently comparing a standard
NS preparation to Juven— a NS that is rich in arginine, glutamine, and b-hydroxy b-methyl butyrate, in cancer patients with cachexia. The intended endpoints of this study, however, are
changes in weight, lean body mass, fatigue, and
QOL. This trial will enroll patients with advanced
stages of different malignancies and is not designed to evaluate survival or any specific cancer
therapy).42
Other approaches include attempts at reproducing our results through similar retrospective
analyses of clinical trials if BNS information is
available and determining whether the effect
demonstrated here is replicated in similarly
treated patients and applicable to other disease
sites and treatment modalities. Integrating
detailed objective NS parameters into future prospective clinical trials and designing such trials
with the intent of evaluating the impact of BNS
on outcome would bring us closer to validating (or
refuting) the implications of our findings. This
would require documentation of routes and duration of supplementation delivery, as well as the
nutritional content of both supplements and normal dietary intake for all patients. Using simple
subjective nutritional assessment scales such as
the Subjective Global Assessment tool43 would
assist the clinician in establishing pretreatment
nutrition status and determining whether this
well-established tool, as an example, correlates
with treatment outcome.
Given the enormous range of possibilities for
the physiologic mechanisms underlying our observations, which our results cannot even begin
to hint at, the next generation of trials might
include evaluation of an array of relevant plasma
cytokines and tumor biomarkers drawn before,
during, and after therapy in an attempt to identify discrete molecular associations with outcome
or differences between patients receiving and not
receiving BNS. Cytokines that are currently thought
to play a role in cachexia and other metabolic
alterations in the patient with cancer include prostaglandin E2 (PGE2), tumor necrosis factor-a
(TNFa), interleukin (IL)-1, IL-6, interferon-g
(IFNg), and proteoglycan 24K.44 Integrated collaboration between nutrition and oncology researchers is sorely needed.
In conclusion, the available published literature
demonstrates that NS is associated with improved
host outcomes, defined as improved QOL and tolerability of treatment. However, here we identify a
Impact of Nutrition Support
clinically meaningful and statistically significant
negative association of BNS on cancer treatment
outcome in a group of patients with HNSCC
treated with definitive radiotherapy, consistent
with other available clinical and preclinical data.
If the bound-to-be-controversial results of this
analysis are confirmed in the future, the benefits
of BNS on the one hand will need to be weighed
against the counter impact of such support on
tumor control. Designing interventions will then
urgently be needed for the nutritionally compromised patient with cancer, currently situated
between this proverbial rock and a hard place.
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