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The effect of oral nutritional supplements on head and neck cancer
0360.3016/S’) $3.00 + .oO (‘opynghl ic 19x9 Pergamon Press plc
In/. J Radmtron Oncology B!ol Phys.. Vol. 16. PP. 1595-1599 Printed in the IJ.S A. All rights reserved.
??Brief Communication
THE EFFECT OF ORAL NUTRITIONAL SUPPLEMENTS ON HEAD AND NECK CANCER CATHY
ARNOLD,
R.D.’
AND MELVYN
P. RICHTER,
M.D.*
‘Department of Surgery, Fox Chase Cancer Center, Central and Shelmire Avenues, Philadelphia, PA ] 9 ] ] ] ; and 2Department of Radiation Medicine, Abington Memorial Hospital. 1200 York Road, Abington, PA 19001 Fifty ambulatory patients with head and neck cancer treated by definitive radiation therapy at the Fox Chase Cancer Center were prospectively studied to determine the effect of oral nutritional supplements on both nutritional status and treatment response. Nutritional supplements maintained serum albumin during and post treatment. Nutritional supplements were shown to increase total protein and total calorie intake rather than displace these nutrients in usual food intake. Equal weight loss occurred in both the supplemented and non-supplemented groups during the observation period of 6 months, with the same or greater amount of weight loss registered 10 weeks after the start of treatment. Food supplements did not affect treatment response or complications, nor did they __ offer any survival advantage. Enteral nutrition, Radiation therapy.
INTRODUCTION
displaces nutrients total intake.
Patients receiving radiation therapy to the head and neck often have compromised nutritional status preceding and during treatment (2,4). Solid food dysphagia, xerostomia, mucositis, and dysguesia are some of the common side effects of therapy which may result in difficulty in oral feeding (5, 7). Commercial liquid formulas given as oral nutritional supplements are frequently used in nutritional management of these patients. Nutritional supplements have been used in several studies involving head and neck cancer patients. Their independent contribution to nutrient intake and nutritional status has not been measured. In a study using 30 patients with epidermoid carcinoma of the head and neck, patients using supplements had less weight loss and maintained serum albumin levels during radiation therapy than a control population (6). Long term effects of nutrition supplementation as an adjunct to radiation therapy have not been evaluated. This study investigated the role of nutritional supplements in maintaining nutritional status and the effect on tolerance to therapy and treatment outcome. In addition, the contribution of kilocalories and protein to total food intake was analyzed to determine whether a supplement
of a usual
METHODS
AND
diet or actually
increases
MATERIALS
Fifty ambulatory patients with cancers of the head and neck planned to receive a potentially curative course of radiation treatment from 5 to 8 weeks were stratified by stage of disease and tumor site. Informed consent was obtained after the nature of the procedure was fully explained. Stratification by site placed patients in either of two categories: Category A tumor site included oral cavity, oropharynx, and nasopharynx and category B tumor site consisted of hypopharynx, larynx, and cervical esophagus. Patients were excluded from entry to the study if both chemotherapy and radiation therapy were planned for treatment. A summary of patient characteristics is given in Table 1. Patients were randomized to supplemented or nonsupplemented groups. Supplemented patients received 960 or 1080 Kcal/day of Sustacal (tm) liquid for 10 weeks beginning on the first day of treatment. All patients were seen on a weekly basis. All patients were encouraged to eat their normal diet ad libitum and were given intensive
M.S. and Samuel Litwin, Ph.D. for statistical analysis: Sherry Griefzu, R.N. for data collection. The nutritional supplement, Sustacal (tm), was supplied by Mead Johnson. Inc., Evansville, Indiana. Accepted for publication I4 December 1988.
Reprint requests to: Cathy Arnold, R.D., Wyeth-Ayerst Laboratories, Clinical Research and Development Department. P.O. Box 8299. Philadelphia, PA 19 10 1. A~knowl~d~emLJnls-The authors would like to thank the following for their assistance: Henry F. Sears, M.D. for encouragement of the project and review of the manuscript; Perry Watts, 1595
1596
I. J. Radiation Oncology 0 Biology 0 Physics
June 1989, Volume 16, Number 6
RESULTS
Table 1. Characteristics of patients NS: n = 23 Disease site Oral cavity Oropharynx SupragIottis Larynx Hypopharynx (cervical esophagus) Nasopharynx Parotid Unknown primary
NNS: n = 27
12 6 2 4
Disease stage I II III IV
5 7 3 8
4 9 10 4
Pretreatment chewing difficulty
6
8
Pretreatment swallowing difficulty
9
9
Definitive surgery I 6 mo. pretreatment
5
8
9 14
20 7
153 -t 35.9 150.9 + 36.6
152.7 -t 35 151.9 + 36
Age Median Range
64.1 34-88
68.3 43-80
cGy dose X Range
6551 3240-7928
6608 497 l-7600
Sex Male Female Weight X usual (lbs.) _%pretreatment
(lbs.)
nutritional counseling which included recommendations of full liquid, pureed, or soft diets when appropriate, using common household foods. Nutritional assessment was performed at pre-treatment, 3, 5, 7, IO-week and 6-month intervals. Body weight, serum albumin, transferrin and 24 hour dietary recalls were recorded at this time. Dietary analysis of energy and protein intake was determined using USDA Handbook No. 456 (1). Radiation side effects were evaluated by a radiation oncologist weekly. Clinical evaluation of radiation reactions were made for each patient. Treatment interruptions due to side effects were totaled. Tumor status was evaluated 3 to 4 months post treatment completion. Patients were considered to have a complete response to therapy if they met the following criteria: (a) disease-free at the primary site, (b) no evidence of adenopathy in the neck nodes, and (c) without metastatic disease.
Effect of supplementation on nutritional status There was no significant difference in weight loss between usual weight and pretreatment weight for patients receiving nutritional supplements (NS) and patients not receiving supplements (NNS), using Mann-Whitney and t-tests. In addition, mean pretreatment weight of 152.7 lbs. for NNS patients and 153.0 lbs. for NS patients were not significantly different. Pretreatment evaluation of visceral protein status was normal for both groups. Mean serum albumin was 4.08 for NNS patients and 4. I 1 for NS patients. Mean serum transfer-rut was 261 for NNS patients and 258 for NS patients (normal range 204 to 360 mg/dl). Pretreatment and 6-month albumin, transferrin, and weight within each group were compared using t tests and sign tests. The NNS patients had a significant decline in albumin, whereas the NS patients did not. Transferrin showed no significant difference in either group. Albumin and transferrin were consistantly within normal limits for both groups at every interval of the study (Figs. 1 and 2). Both groups lost weight during treatment; there was no significant difference between groups at each week of nutritional assessment, although percentage of weight loss was less for NS patients through week 7 of supplementation. Both groups tended to lose the same or greater amount of weight after cessation of treatment using paired difference tests and sign tests. Average weight loss between weeks 10 and 26 was 6.14 lbs. for NNS, 8.60 lbs. for NS, and 7.19 lbs. for both (Fig. 3).
Contribution of supplement to nutrient intake To determine the effect of supplementation on dietary intake, each subject’s calorie and protein intake was totaled for weeks 3, 5, 7 and 10. Statistical calculations are
NNS
8 @i P=
b
0
wk 3
nk 5
wk 7
rk 10
6 In08
Time Fig. 1. Mean serum albumin radiotherapy.
(gm/dl) before, during and post
Effect of supplements 0 C. ARNOLD
AND
1597
M. P. RICHTER
Table 2. Mean energy and protein intake of patients weeks 3, 5,7 and IO*
NS Total kcal Residual kcal$
b
9.
$9-
-
z
N
NS
A
NNS
0
Pre
wk 3
Irk 5
wk 7
6 mos
wk 10
p-value (one-tailed)?
NNS
1929.8 ?I 605.3 1624.3 + 528.7 1392.4 f 593.5 1604.3 + 511.4
Total protein (gm) Residual protein (gm)S:
during
0.035 0.048
88.4 f 31.9
66.9 -t 26.1
0.005
55.4 f 27. I
65.7 f 25.0
0.035
* Calculation based on mean intake of nutrients for weeks 3, 5. 7 and 10 per individual. 7 Mann-Whitney test. $ Residual kcal = Total kcal - kcal derived from supplement. $ Residual protein = Total protein - protein derived from
supplement.
Time Fig. 2. Mean serum transferrin radiotherapy.
(mg/dl) before, during and post
based on the means of total calories, total protein, residual calories (total calories - supplementary calories) and residual protein (total protein - supplementary protein) (Table 2). Mann-Whitney tests showed significant increase in mean total protein for NS patients of an additional 22 grams above NNS patients (p = 0.01) and a marginally significant result in residual protein where protein derived from usual diet is 10 grams less than protein in NNS patients (p = 0.07). Total energy intake for NS patients is 300 kilocalories greater than that of NNS patients (marginally significant, p = 0.07). Residual kilocalories between the two groups were not significant. A Mahalinobis score was determined in the following manner. It is based on constructing one linear regression per individual over weeks 3, 5, 7, and 10, for each of the
following variables: total kilocalories, residual kilocalories, total protein, and residual protein. Each regression line yields a score for “a” and “b”, as in y = a + bx, per individual. The points are plotted and the resulting scatter plots for NS and NNS patients were compared. Significance of the scores was then determined by a sampled permutation test of 99 runs, and the resulting scores were ranked. The actual results were then compared to those randomly generated. The Mahalinobis score addresses the question of whether supplementation added to nutrient content in the diet, or substituted for nutrients which were ordinarily eaten. Total kilocalories and total protein for NS and NNS groups were significantly different (p = 0.02, two-tailed), but residual kilocalories and residual protein were not. Therefore, nutritional supplements add to the nutrient content of the diet. Figures 4 and 5 indicate that some displacement of nutrients occurs, but the overall effect to the diet is to increase kilocalories and protein in the supplemented patient.
El 0
El I cl
NS NNS
m
Pre
wk 3
nk 5
wk 7
Irk 10
6 mos
Time Fig. 3. Percentage therapy.
NS sup
NNS
Pre
nk 3
of weight loss before, during and post radioFig. 4. Contribution
rk 5 rk 7 Time
of supplement
wk 10 6 mos
to mean energy intake.
1. J. Radiation Oncology 0 Biology 0 Physics
difference patients.
EM0 NS Sup
June 1989, Volume 16, Number 6
between
supplemented
and non-supplemented
NNS
DISCUSSION
P=e
wk 3
wk 5
wk 7
wk 10
6 mos
Time Fig. 5. Contribution
of supplement
of mean protein intake.
None of the NS patients took the entire recommended volume of the supplement; only 7 NS patients took at least 80 percent of the supplement. One patient in the NNS group took a supplement during the first 10 weeks. In the treatment group, mean consumption of supplement by males was 67% of the recommended volume of supplement, and for females 56% of the recommended volume of supplement. None of the patients received tube feedings in the first 10 weeks of the study. At 6 months, 2 NNS patients required tube feedings, and 3 NNS patients were receiving oral supplements. Two NS patients were placed on a tube feeding, and 2 NS patients continued to use the oral supplement at 6 months.
Response to radiation therapy Treatment outcome. Patients were categorized as having a complete response to treatment if cleared of tumor at primary site and necks, and disease-free at other locations. Patients who did not meet these criteria were listed as having an incomplete response (Table 3). Numbers in parentheses indicate patient deaths. There was no significant difference in tumor response between the two groups. Survival analysis of NS and NNS patients show no significant difference for patients using a nutritional supplement. Treatment complications and interruptions. Incidence of mucositis, pharyngitis, esophagitis, and other side effects were not significantly different in both groups. With respect to treatment interruptions, there was no significant Table
3. Tumor status at 3 months post treatment
Complete response Progressive disease Dead
NS
NNS
16 4 3
14 13 0
Enteral nutritional support of head and neck cancer patients has been evaluated in several studies (5, 1 1, 13). A retrospective trial of tube feeding in head and neck cancer patients with Stages III and IV tumors has shown less weight loss in patients receiving tube feeding, but offered no significant survival advantage. Complications in 7 out of 26 patients secondary to tube feeding were also noted (13). Daly et al., in a prospective study using tube fed patients and patients receiving optimal oral nutrition, including a variety of supplements, found tube fed patients with cancers of the oral cavity as well as oropharyngeal, hypopharyngeal, laryngeal, and recurrent nasopharyngeal carcinomas had less weight loss than orally fed patients. Thirty-seven out of forty patients in this study were Stage III or IV (5). In another paper, using the same study patients, median serum albumin after a decline in week 4 of treatment, returned to pretreatment levels in only 4 out of 16 patients in both groups. There was no significant difference in serum albumin during and 1 month after radiation treatment (10). Tube feeding did not reduce toxicity to therapy, nor did it affect tumor response or offer any survival advantage (5). A prospective study of 3 1 head and neck cancer patients of unknown stage found a mean weight loss of 10 percent 1 month after cessation of radiation therapy. Serum albumin was less than 90 percent of standard value in 10 out of 26 patients. This occurred despite nutritional counseling. No data was available for the number of patients receiving oral supplements; supplements were not uniformly given to all patients (1 1). Tube feedings used in two of the three studies minimized, but did not prevent weight loss. In all studies, weight loss continued to occur post-treatment. In addition, serum albumin declined in some tube fed and orally fed patients. Depressed serum albumin has been associated with a greater incidence of morbidity and mortality in hospitalized patients ( 14). Several studies of surgical populations report similar findings (9, 12). Maintenance of serum albumin levels therefore is desirable, particularly for the patient who fails radiation therapy and requires surgery for progressive disease. In this study, serum albumin was significantly greater at 6 months in the NS patients as compared to the NNS patients. The differences in serum albumin levels may be due to the following factors. Patients with Stage III and IV head and neck carcinomas may have more anatomically extensive disease which may have a priori a negative impact on nutritional status of the host; two of the three studies had enlisted primarily these stages of disease. In contrast, one half of the patients in the present study were Stage I or II. Pretreatment weight loss was seen by Pezner
Effectof supplements ??C. ARNOLD
and Daly, whereas there was no significant difference in baseline and usual weight in this study. Absence of pretreatment weight loss may be atypical of a head and neck cancer population. Malnutrition secondary to heavy alcohol consumption is a common feature in these patients. Although 18 patients admitted heavy alcohol use, pretreatment nutritional status was not impaired. Note that this is a middle class population in which the access to and acquisition of nutritious foodstuffs is readily available. These patients were highly motivated to maintain an adequate intake throughout treatment and were therefore cooperative in drinking the supplement. Patients in the control group had more progressive disease at 3 to 4 months than did those in the treatment group, although the difference was not statistically significant. Metabolic alterations have been reported in the tumor-bearing host which may contribute to depressed serum albumin levels (2). However, in a study comparing the metabolic effects of enteral nutrition in malnourished patients with and without cancer, nutritional support suppressed both endogenous glucose production and whole body protein catabolism in tumor-bearing and nontumor-bearing hosts (8). This suggests that the control patients with progressive disease who initially were not malnourished, may have maintained a better nutritional status if given the supplemental feeding.
AND
M. P. RICHTER
1599
In summary, oral nutritional supplements used in conjunction with nutrition counseling, maintained serum albumin levels in well nourished head and neck cancer patients as compared to a control group. This suggests that enteral support is most effective in preserving visceral protein levels if initiated before a decline in nutritional status is evident. Thus, all patients in this population should be considered candidates for nutritional intervention. Supplementation increased rather than displaced the nutrient content of the usual diet. Oral supplementation did not affect survival status, tumor response, side effects from treatment, or treatment interruptions, when compared to controls. Weight loss occurred despite supplementation during and after treatment. Further research might address this problem in several ways. Post-treatment weight loss might be decreased with continuing nutritional intervention after cessation of therapy. It is possible that a change in the formulation of commercial products may encourage greater supplemental intake and weight maintenance. Unfortunately, most commonly used formulas, including the product used in this study, have a milky quality which exacerbates mucous production for many patients. Development of a clear liquid, non-acidic supplement of comparable nutrient density would be suitable for trial in this population.
REFERENCES 1. Adams, C. F. Nutritive values of american foods in common units. USDA Agricultural Handbook No. 456; 1975. 2. Brennan, M. F. Uncomplicated starvation versus cancer cachexia. Cancer Res. 37:2359-2364; 1977. 3. Chencharick. J. D.; Mossman, K. L. Nutritional consequences of the radiotherapy of head and neck cancer. Cancer 5181 I-815; 1983. 4. Crossland, S. G.; Higgins, G. C. Nutritional supplements in head and neck radiation therapy (Abstr.). J.P.E.N. 1:27: 1977. 5. Daly, J. M.; Hearne, B.; Dunaj, J.; LePorte, B.; Vikram, B.: Strong, E.; Green, M.; Muggio, F.; Groshen, S.; DeCosse, J. J. Nutritional rehabilitation in patients with advanced head and neck cancer receiving radiation therapy. Am. J. Surg. 1485 14-520; 1984. 6. DeWys, W. D.; Herbst, S. H. Oral feeding in the nutritional management of the cancer patient. Cancer Res. 37:24292431: 1977. 7. Donaldson. S. S. Nutritional consequences of radiotherapy. Cancer Res. 3712407-2413; 1977. 8. Dresler, C. M.; Jeevanandam, M.; Brennan, M. F. Metabolic efficacy of enteral feeding in malnourished cancer and noncancer patients. Metabolism 36:82-88; 1987.
9. Harvey, K. B.; Bothe, A. Jr.; Blackburn, G. L. Nutritional assessment and patient outcome during oncologic therapy. Cancer 43:2065-2069; 1979. 10. Heame, B. E.; Dunaj, J. M.; Daly, J. M.; Strong, E.: Vikram, B.; LePorte, B.: DeCosse, J. J. Enteral nutritional support in head and neck cancer: tube vs. oral feeding during radiation therapy. J. Am. Diet. Assoc. 85:669-677: 198.5.
I I. Johnson,
C. A.; Keane, T. J.; Prudo, S. M. Weight loss in patients receiving radical radiation therapy for head and neck cancer: a prospective study. J.P.E.N. 6:399-402; 1982.
12. Mullen, J. L.; Gertner. M. H.; Buzby, G. P. Implications of malnutrition in the surgical patient. Arch. Surg. 1 14: I2 I 125: 1979. J. 0.; 13. Pezner, R. D.; Archambeau, W. A.; Thayer, W.; Hill, L. R. Tube tional support in patients receiving advanced head and neck cancer. Int. Phys. I3:935-939; 1987.
Lipsett, J. A.; Kokal, feeding enteral nutriradiation therapy for J. Radiat. Oncol. Biol.
14. Seltzer, M. H.; Bastidas, J. A.: Cooper, D. M.: Engler, P.: Slocum, B.: Fletcher, H. S. Instant nutritional assessment. J.P.E.N. 3:157-159; 1979.
In/. J Radmtron Oncology B!ol Phys.. Vol. 16. PP. 1595-1599 Printed in the IJ.S A. All rights reserved.
??Brief Communication
THE EFFECT OF ORAL NUTRITIONAL SUPPLEMENTS ON HEAD AND NECK CANCER CATHY
ARNOLD,
R.D.’
AND MELVYN
P. RICHTER,
M.D.*
‘Department of Surgery, Fox Chase Cancer Center, Central and Shelmire Avenues, Philadelphia, PA ] 9 ] ] ] ; and 2Department of Radiation Medicine, Abington Memorial Hospital. 1200 York Road, Abington, PA 19001 Fifty ambulatory patients with head and neck cancer treated by definitive radiation therapy at the Fox Chase Cancer Center were prospectively studied to determine the effect of oral nutritional supplements on both nutritional status and treatment response. Nutritional supplements maintained serum albumin during and post treatment. Nutritional supplements were shown to increase total protein and total calorie intake rather than displace these nutrients in usual food intake. Equal weight loss occurred in both the supplemented and non-supplemented groups during the observation period of 6 months, with the same or greater amount of weight loss registered 10 weeks after the start of treatment. Food supplements did not affect treatment response or complications, nor did they __ offer any survival advantage. Enteral nutrition, Radiation therapy.
INTRODUCTION
displaces nutrients total intake.
Patients receiving radiation therapy to the head and neck often have compromised nutritional status preceding and during treatment (2,4). Solid food dysphagia, xerostomia, mucositis, and dysguesia are some of the common side effects of therapy which may result in difficulty in oral feeding (5, 7). Commercial liquid formulas given as oral nutritional supplements are frequently used in nutritional management of these patients. Nutritional supplements have been used in several studies involving head and neck cancer patients. Their independent contribution to nutrient intake and nutritional status has not been measured. In a study using 30 patients with epidermoid carcinoma of the head and neck, patients using supplements had less weight loss and maintained serum albumin levels during radiation therapy than a control population (6). Long term effects of nutrition supplementation as an adjunct to radiation therapy have not been evaluated. This study investigated the role of nutritional supplements in maintaining nutritional status and the effect on tolerance to therapy and treatment outcome. In addition, the contribution of kilocalories and protein to total food intake was analyzed to determine whether a supplement
of a usual
METHODS
AND
diet or actually
increases
MATERIALS
Fifty ambulatory patients with cancers of the head and neck planned to receive a potentially curative course of radiation treatment from 5 to 8 weeks were stratified by stage of disease and tumor site. Informed consent was obtained after the nature of the procedure was fully explained. Stratification by site placed patients in either of two categories: Category A tumor site included oral cavity, oropharynx, and nasopharynx and category B tumor site consisted of hypopharynx, larynx, and cervical esophagus. Patients were excluded from entry to the study if both chemotherapy and radiation therapy were planned for treatment. A summary of patient characteristics is given in Table 1. Patients were randomized to supplemented or nonsupplemented groups. Supplemented patients received 960 or 1080 Kcal/day of Sustacal (tm) liquid for 10 weeks beginning on the first day of treatment. All patients were seen on a weekly basis. All patients were encouraged to eat their normal diet ad libitum and were given intensive
M.S. and Samuel Litwin, Ph.D. for statistical analysis: Sherry Griefzu, R.N. for data collection. The nutritional supplement, Sustacal (tm), was supplied by Mead Johnson. Inc., Evansville, Indiana. Accepted for publication I4 December 1988.
Reprint requests to: Cathy Arnold, R.D., Wyeth-Ayerst Laboratories, Clinical Research and Development Department. P.O. Box 8299. Philadelphia, PA 19 10 1. A~knowl~d~emLJnls-The authors would like to thank the following for their assistance: Henry F. Sears, M.D. for encouragement of the project and review of the manuscript; Perry Watts, 1595
1596
I. J. Radiation Oncology 0 Biology 0 Physics
June 1989, Volume 16, Number 6
RESULTS
Table 1. Characteristics of patients NS: n = 23 Disease site Oral cavity Oropharynx SupragIottis Larynx Hypopharynx (cervical esophagus) Nasopharynx Parotid Unknown primary
NNS: n = 27
12 6 2 4
Disease stage I II III IV
5 7 3 8
4 9 10 4
Pretreatment chewing difficulty
6
8
Pretreatment swallowing difficulty
9
9
Definitive surgery I 6 mo. pretreatment
5
8
9 14
20 7
153 -t 35.9 150.9 + 36.6
152.7 -t 35 151.9 + 36
Age Median Range
64.1 34-88
68.3 43-80
cGy dose X Range
6551 3240-7928
6608 497 l-7600
Sex Male Female Weight X usual (lbs.) _%pretreatment
(lbs.)
nutritional counseling which included recommendations of full liquid, pureed, or soft diets when appropriate, using common household foods. Nutritional assessment was performed at pre-treatment, 3, 5, 7, IO-week and 6-month intervals. Body weight, serum albumin, transferrin and 24 hour dietary recalls were recorded at this time. Dietary analysis of energy and protein intake was determined using USDA Handbook No. 456 (1). Radiation side effects were evaluated by a radiation oncologist weekly. Clinical evaluation of radiation reactions were made for each patient. Treatment interruptions due to side effects were totaled. Tumor status was evaluated 3 to 4 months post treatment completion. Patients were considered to have a complete response to therapy if they met the following criteria: (a) disease-free at the primary site, (b) no evidence of adenopathy in the neck nodes, and (c) without metastatic disease.
Effect of supplementation on nutritional status There was no significant difference in weight loss between usual weight and pretreatment weight for patients receiving nutritional supplements (NS) and patients not receiving supplements (NNS), using Mann-Whitney and t-tests. In addition, mean pretreatment weight of 152.7 lbs. for NNS patients and 153.0 lbs. for NS patients were not significantly different. Pretreatment evaluation of visceral protein status was normal for both groups. Mean serum albumin was 4.08 for NNS patients and 4. I 1 for NS patients. Mean serum transfer-rut was 261 for NNS patients and 258 for NS patients (normal range 204 to 360 mg/dl). Pretreatment and 6-month albumin, transferrin, and weight within each group were compared using t tests and sign tests. The NNS patients had a significant decline in albumin, whereas the NS patients did not. Transferrin showed no significant difference in either group. Albumin and transferrin were consistantly within normal limits for both groups at every interval of the study (Figs. 1 and 2). Both groups lost weight during treatment; there was no significant difference between groups at each week of nutritional assessment, although percentage of weight loss was less for NS patients through week 7 of supplementation. Both groups tended to lose the same or greater amount of weight after cessation of treatment using paired difference tests and sign tests. Average weight loss between weeks 10 and 26 was 6.14 lbs. for NNS, 8.60 lbs. for NS, and 7.19 lbs. for both (Fig. 3).
Contribution of supplement to nutrient intake To determine the effect of supplementation on dietary intake, each subject’s calorie and protein intake was totaled for weeks 3, 5, 7 and 10. Statistical calculations are
NNS
8 @i P=
b
0
wk 3
nk 5
wk 7
rk 10
6 In08
Time Fig. 1. Mean serum albumin radiotherapy.
(gm/dl) before, during and post
Effect of supplements 0 C. ARNOLD
AND
1597
M. P. RICHTER
Table 2. Mean energy and protein intake of patients weeks 3, 5,7 and IO*
NS Total kcal Residual kcal$
b
9.
$9-
-
z
N
NS
A
NNS
0
Pre
wk 3
Irk 5
wk 7
6 mos
wk 10
p-value (one-tailed)?
NNS
1929.8 ?I 605.3 1624.3 + 528.7 1392.4 f 593.5 1604.3 + 511.4
Total protein (gm) Residual protein (gm)S:
during
0.035 0.048
88.4 f 31.9
66.9 -t 26.1
0.005
55.4 f 27. I
65.7 f 25.0
0.035
* Calculation based on mean intake of nutrients for weeks 3, 5. 7 and 10 per individual. 7 Mann-Whitney test. $ Residual kcal = Total kcal - kcal derived from supplement. $ Residual protein = Total protein - protein derived from
supplement.
Time Fig. 2. Mean serum transferrin radiotherapy.
(mg/dl) before, during and post
based on the means of total calories, total protein, residual calories (total calories - supplementary calories) and residual protein (total protein - supplementary protein) (Table 2). Mann-Whitney tests showed significant increase in mean total protein for NS patients of an additional 22 grams above NNS patients (p = 0.01) and a marginally significant result in residual protein where protein derived from usual diet is 10 grams less than protein in NNS patients (p = 0.07). Total energy intake for NS patients is 300 kilocalories greater than that of NNS patients (marginally significant, p = 0.07). Residual kilocalories between the two groups were not significant. A Mahalinobis score was determined in the following manner. It is based on constructing one linear regression per individual over weeks 3, 5, 7, and 10, for each of the
following variables: total kilocalories, residual kilocalories, total protein, and residual protein. Each regression line yields a score for “a” and “b”, as in y = a + bx, per individual. The points are plotted and the resulting scatter plots for NS and NNS patients were compared. Significance of the scores was then determined by a sampled permutation test of 99 runs, and the resulting scores were ranked. The actual results were then compared to those randomly generated. The Mahalinobis score addresses the question of whether supplementation added to nutrient content in the diet, or substituted for nutrients which were ordinarily eaten. Total kilocalories and total protein for NS and NNS groups were significantly different (p = 0.02, two-tailed), but residual kilocalories and residual protein were not. Therefore, nutritional supplements add to the nutrient content of the diet. Figures 4 and 5 indicate that some displacement of nutrients occurs, but the overall effect to the diet is to increase kilocalories and protein in the supplemented patient.
El 0
El I cl
NS NNS
m
Pre
wk 3
nk 5
wk 7
Irk 10
6 mos
Time Fig. 3. Percentage therapy.
NS sup
NNS
Pre
nk 3
of weight loss before, during and post radioFig. 4. Contribution
rk 5 rk 7 Time
of supplement
wk 10 6 mos
to mean energy intake.
1. J. Radiation Oncology 0 Biology 0 Physics
difference patients.
EM0 NS Sup
June 1989, Volume 16, Number 6
between
supplemented
and non-supplemented
NNS
DISCUSSION
P=e
wk 3
wk 5
wk 7
wk 10
6 mos
Time Fig. 5. Contribution
of supplement
of mean protein intake.
None of the NS patients took the entire recommended volume of the supplement; only 7 NS patients took at least 80 percent of the supplement. One patient in the NNS group took a supplement during the first 10 weeks. In the treatment group, mean consumption of supplement by males was 67% of the recommended volume of supplement, and for females 56% of the recommended volume of supplement. None of the patients received tube feedings in the first 10 weeks of the study. At 6 months, 2 NNS patients required tube feedings, and 3 NNS patients were receiving oral supplements. Two NS patients were placed on a tube feeding, and 2 NS patients continued to use the oral supplement at 6 months.
Response to radiation therapy Treatment outcome. Patients were categorized as having a complete response to treatment if cleared of tumor at primary site and necks, and disease-free at other locations. Patients who did not meet these criteria were listed as having an incomplete response (Table 3). Numbers in parentheses indicate patient deaths. There was no significant difference in tumor response between the two groups. Survival analysis of NS and NNS patients show no significant difference for patients using a nutritional supplement. Treatment complications and interruptions. Incidence of mucositis, pharyngitis, esophagitis, and other side effects were not significantly different in both groups. With respect to treatment interruptions, there was no significant Table
3. Tumor status at 3 months post treatment
Complete response Progressive disease Dead
NS
NNS
16 4 3
14 13 0
Enteral nutritional support of head and neck cancer patients has been evaluated in several studies (5, 1 1, 13). A retrospective trial of tube feeding in head and neck cancer patients with Stages III and IV tumors has shown less weight loss in patients receiving tube feeding, but offered no significant survival advantage. Complications in 7 out of 26 patients secondary to tube feeding were also noted (13). Daly et al., in a prospective study using tube fed patients and patients receiving optimal oral nutrition, including a variety of supplements, found tube fed patients with cancers of the oral cavity as well as oropharyngeal, hypopharyngeal, laryngeal, and recurrent nasopharyngeal carcinomas had less weight loss than orally fed patients. Thirty-seven out of forty patients in this study were Stage III or IV (5). In another paper, using the same study patients, median serum albumin after a decline in week 4 of treatment, returned to pretreatment levels in only 4 out of 16 patients in both groups. There was no significant difference in serum albumin during and 1 month after radiation treatment (10). Tube feeding did not reduce toxicity to therapy, nor did it affect tumor response or offer any survival advantage (5). A prospective study of 3 1 head and neck cancer patients of unknown stage found a mean weight loss of 10 percent 1 month after cessation of radiation therapy. Serum albumin was less than 90 percent of standard value in 10 out of 26 patients. This occurred despite nutritional counseling. No data was available for the number of patients receiving oral supplements; supplements were not uniformly given to all patients (1 1). Tube feedings used in two of the three studies minimized, but did not prevent weight loss. In all studies, weight loss continued to occur post-treatment. In addition, serum albumin declined in some tube fed and orally fed patients. Depressed serum albumin has been associated with a greater incidence of morbidity and mortality in hospitalized patients ( 14). Several studies of surgical populations report similar findings (9, 12). Maintenance of serum albumin levels therefore is desirable, particularly for the patient who fails radiation therapy and requires surgery for progressive disease. In this study, serum albumin was significantly greater at 6 months in the NS patients as compared to the NNS patients. The differences in serum albumin levels may be due to the following factors. Patients with Stage III and IV head and neck carcinomas may have more anatomically extensive disease which may have a priori a negative impact on nutritional status of the host; two of the three studies had enlisted primarily these stages of disease. In contrast, one half of the patients in the present study were Stage I or II. Pretreatment weight loss was seen by Pezner
Effectof supplements ??C. ARNOLD
and Daly, whereas there was no significant difference in baseline and usual weight in this study. Absence of pretreatment weight loss may be atypical of a head and neck cancer population. Malnutrition secondary to heavy alcohol consumption is a common feature in these patients. Although 18 patients admitted heavy alcohol use, pretreatment nutritional status was not impaired. Note that this is a middle class population in which the access to and acquisition of nutritious foodstuffs is readily available. These patients were highly motivated to maintain an adequate intake throughout treatment and were therefore cooperative in drinking the supplement. Patients in the control group had more progressive disease at 3 to 4 months than did those in the treatment group, although the difference was not statistically significant. Metabolic alterations have been reported in the tumor-bearing host which may contribute to depressed serum albumin levels (2). However, in a study comparing the metabolic effects of enteral nutrition in malnourished patients with and without cancer, nutritional support suppressed both endogenous glucose production and whole body protein catabolism in tumor-bearing and nontumor-bearing hosts (8). This suggests that the control patients with progressive disease who initially were not malnourished, may have maintained a better nutritional status if given the supplemental feeding.
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M. P. RICHTER
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In summary, oral nutritional supplements used in conjunction with nutrition counseling, maintained serum albumin levels in well nourished head and neck cancer patients as compared to a control group. This suggests that enteral support is most effective in preserving visceral protein levels if initiated before a decline in nutritional status is evident. Thus, all patients in this population should be considered candidates for nutritional intervention. Supplementation increased rather than displaced the nutrient content of the usual diet. Oral supplementation did not affect survival status, tumor response, side effects from treatment, or treatment interruptions, when compared to controls. Weight loss occurred despite supplementation during and after treatment. Further research might address this problem in several ways. Post-treatment weight loss might be decreased with continuing nutritional intervention after cessation of therapy. It is possible that a change in the formulation of commercial products may encourage greater supplemental intake and weight maintenance. Unfortunately, most commonly used formulas, including the product used in this study, have a milky quality which exacerbates mucous production for many patients. Development of a clear liquid, non-acidic supplement of comparable nutrient density would be suitable for trial in this population.
REFERENCES 1. Adams, C. F. Nutritive values of american foods in common units. USDA Agricultural Handbook No. 456; 1975. 2. Brennan, M. F. Uncomplicated starvation versus cancer cachexia. Cancer Res. 37:2359-2364; 1977. 3. Chencharick. J. D.; Mossman, K. L. Nutritional consequences of the radiotherapy of head and neck cancer. Cancer 5181 I-815; 1983. 4. Crossland, S. G.; Higgins, G. C. Nutritional supplements in head and neck radiation therapy (Abstr.). J.P.E.N. 1:27: 1977. 5. Daly, J. M.; Hearne, B.; Dunaj, J.; LePorte, B.; Vikram, B.: Strong, E.; Green, M.; Muggio, F.; Groshen, S.; DeCosse, J. J. Nutritional rehabilitation in patients with advanced head and neck cancer receiving radiation therapy. Am. J. Surg. 1485 14-520; 1984. 6. DeWys, W. D.; Herbst, S. H. Oral feeding in the nutritional management of the cancer patient. Cancer Res. 37:24292431: 1977. 7. Donaldson. S. S. Nutritional consequences of radiotherapy. Cancer Res. 3712407-2413; 1977. 8. Dresler, C. M.; Jeevanandam, M.; Brennan, M. F. Metabolic efficacy of enteral feeding in malnourished cancer and noncancer patients. Metabolism 36:82-88; 1987.
9. Harvey, K. B.; Bothe, A. Jr.; Blackburn, G. L. Nutritional assessment and patient outcome during oncologic therapy. Cancer 43:2065-2069; 1979. 10. Heame, B. E.; Dunaj, J. M.; Daly, J. M.; Strong, E.: Vikram, B.; LePorte, B.: DeCosse, J. J. Enteral nutritional support in head and neck cancer: tube vs. oral feeding during radiation therapy. J. Am. Diet. Assoc. 85:669-677: 198.5.
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C. A.; Keane, T. J.; Prudo, S. M. Weight loss in patients receiving radical radiation therapy for head and neck cancer: a prospective study. J.P.E.N. 6:399-402; 1982.
12. Mullen, J. L.; Gertner. M. H.; Buzby, G. P. Implications of malnutrition in the surgical patient. Arch. Surg. 1 14: I2 I 125: 1979. J. 0.; 13. Pezner, R. D.; Archambeau, W. A.; Thayer, W.; Hill, L. R. Tube tional support in patients receiving advanced head and neck cancer. Int. Phys. I3:935-939; 1987.
Lipsett, J. A.; Kokal, feeding enteral nutriradiation therapy for J. Radiat. Oncol. Biol.
14. Seltzer, M. H.; Bastidas, J. A.: Cooper, D. M.: Engler, P.: Slocum, B.: Fletcher, H. S. Instant nutritional assessment. J.P.E.N. 3:157-159; 1979.