MALNUTRITION I N CHILDREN W I T H CANCER

Incidence and Consequence

J A N VAN EYS, PHD, MD

Overt malnutrition in children with cancer is seen with surprising frequency:

up to 37.5%in a group of patients with disease metastatic to or from bone, and
17.5% in a group of newly diagnosed patients with abdominal or pelvic tumors.
It appears more frequent in some cancers. e.g., Ewing’s sarcoma, than in others,
e.g., osteosarcoma. Criteria for diagnosis of overt malnutrition are applicable
to the child with cancer. Such overt malnutrition can be successfully and safely
treated with intravenous hyperalimentation (IVH). Marginal malnutrition is
a state that can be inferred from clinical behavior, although it cannot be objec-
tively diagnosed as yet. Early data suggest that deterioration to overt malnutri-
tion can be averted through IVH. Such nutritional intervention may increase
chemotherapeutic tolerance and improve immune defenses. Since childhood
cancer is beginning to frequently show excellent outcome, the association of
malnutrition with progressive disease strongly suggests investigation of the
role of nutritional support.
Cancer 43:2030-2035, 1979.

T o FEED A C H I L D is a basic instinct. T h a t

malnutrition among children exists
world wide is considered a major tragedy. I t is
considered ethically and morally reprehen-
sible that the “haves” d o not support the
children of the “have-nots” in this world. Yet
American medicine has persistently ignored
malnutrition in the child with cancer. T h e
malnourished state was considered part of
the symptom complex of progressive an d ac-
tive cancer. It is surprising that only recently
has nutrition been recognized as an isolatable
problem, quite apart from the cancer-just
as infection can and must be diagnosed and
treated or thrombocytopenic bleeding can
and must be dealt with. Thisignoringof nutri-
tion is especially tragic since the stakes in child-
hood malignancies are high-cancer is now a
chronic disease in children and no longer in-
dicates certain demise. This paper will sum-
marize the state of pediatric cancer care an d
the results which are achievable. T h e in-
Presented at the American Cancer Society and Na-
tional Cancer Institute National Conference on Nutrition
i n Cancer, June 29-July 1, 1978, Seattle, Washington.
From the Department of Pediatrics, T h e University of
Texas System Cancer Center, M. D. Anderson Hospital
and T u m o r Institute. Houston, Texas.
Supported in part by contract #N01-CP-65794 lrom
the Diet, Nutrition. and Cancer Program.
Address for reprints: Jan van Eys, MD, Univ. of Texas
System Cancer Center. M. D. Anderson Hospital and
T u m o r Institute. Houston, T X 77030.
Accepted for publication September 12, 1978.
0008-543X/79/0500/2030 $0.80 0 American Cancer Society
2030
cidence of malnutrition will be examined a n d
the impact malnutrition has o n cure a n d out-
come briefly discussed with the limited data
so far available. T h e information summarized
here is simple, and may appear obvious. But
w e have often ignored the obvious or per-
ceived the simple as insolubly complex.
CHILDHOOD THERAPY
CANCER RESULTS
T h e types of cancers seen in children a r e
quantitatively and qualitatively different from
those seen in adults. Chemotherapy has been
especially effective in treating cancers in
children so that the outlook of children with
cancers is not anymore invariably fatal-
rather the converse, children live more often
than not. In 1969 there were 70 new patients,
not previously treated, who were seen at the
M. D. Anderson Hospital a n d T u m o r Insti-
tute, Department of Pediatrics. Five years
later 54% are disease free, and 50% have
never had evidence of recurrence. Even more
importantly, of 28 patients first seen in 1969
who w e r e treated elsewhere, 7 lived disease
free i n excess of 3 years. T h is salvage rate is
seen equally well in such diagnoses as Wilms’
tumor.lg T h e question, therefore, is not any
more how do w e succeed, but why do we fail in
some children. Even relapse does not neces-
sarily mean that the battle is lost.
One of the main problems in children with
cancer is malnutrition, and this is more com-
No. 5 MALNUTRITION
I N CHILDREN
W I T H CA van Eys 203 1

1. Nutritional Data for Neuroblastoma Patients, Stage I V

TABLE

Therapy
Patients courses Nutritional outcome
~~ ~~ ~

Malnourished
IVH 3 28 3/3 well nourished, IVH stopped
113 again became malnourished
Seemingly well nourished
Control 2 10 112 became malnourished
IVH 3 10 3/3 remained well nourished

monly seen in children who have active dis- grey zone of marginal nutrition in which the
ease, especially in relapse. It is therefore vital criteria for overt malnutrition are not met but
that we pursue an active investigation of the in which body stores are depleted to the
interrelationship of diet, nutrition and cancer degree that overt malnutrition will follow with
in children to see if nutritional support will near certainty if the clinical course is not al-
allow for improvement in outcome. tered. There are, to date, no laboratory tests
that infallibly diagnose and define this patient
DEFINITION OF MALNUTRITION set. I t can be stated that seemingly well-
nourished patients include marginally mal-
There is, by definition, a state of adequate nourished patients as well as truly adequately
nutrition in which the absolute and relative fed patients. Table 1 illustrates the problem in
quantity of all nutrients is sufficient for all practice. A series of 8 patients with neuro-
needs of growth and development. At the blastoma, stage IV, is summarized. This group
other extreme there is a state in which the in- of patients is comparable in that all were
take of nutrients is clearly insufficient. A pa- treated with one chemotherapy protocol, and
tient thus can be adequately nourished or all except 1 were not previously treated with
overtly malnourished. We generally see other forms of chemotherapy. Three patients
protein-calorie malnutrition variably com- were overtly malnourished and treated im-
pounded with specific nutrient defects. The mediately with intravenous hyperalimenta-
diagnosis of overt malnutrition is simple. tion. All 3 became seemingly well nourished
There is inadequate growth, and weight for in spite of intensive chemotherapy. Discon-
height is often well below the 20th percentile tinuation of IVH support resulted in return
of the national standards and/or a serum al- of the malnourished state in 1. Of the seem-
bumin value two standard deviations below ingly well-nourished patients, 2 were man-
norm for age. This lower limit is generally set aged by conventional feeding, and 1 became
at C3.0 g/dl. Anthropometry allows measure- rapidly malnourished. Three patients were
ment of skinfold thickness which gives a meas- treated with IVH and remained well nour-
ure of fat reserves, but is not generally used ished. In this miniseries, malnutrition was fre-
in children because adequate standards are
not available. TABLE 2. Incidence of Malnutrition: Cooperative
Overt malnutrition is diagnosable as a Study of Hyperalimentation*
separate entity. The presence of cancer or its
activity is irrelevant for diagnosis except that Patient status Number Percent
cancer seems to be associated with malnutri- Apparently well nourished 33 82.5
tion. T h e criteria for diagnosis of overt mal- Randomized to
nutrition are as applicable in a child with can- hyperalimentation 15
cer as they are in all children who satisfy Randomized to control 13
Nonrandomized 5
these criteria. The patient who is vigorously Overtly malnourished 7 17.5
rehabilitated will gain weight, increase serum Crossover (3/8)t
albumin, and become well nourished. Re- TOTAL 40 100
moval of the increased nutritional intake
results in return to the malnourished state if * Patients with abdominal tumors who were newly
diagnosed and who were to receive abdominal irradiation.
the etiology is not removed. t 3 Patients out of 8 who have complete data at this
When there is an overtly malnourished and time crossed over from control-apparently well nour-
an adequately nourished state there must be a ished to malnourished.
2032 May Supplrmmt 1979
CANCER VOl. 43

TABLE
3. Incidence of Malnutrition, 'M. D. Anderson Hospital

Seemingly well
nourished

Oral
Total patient Overtly feed- . Hyperali-
Diagnosis number* malnourished ing . mentation

Ewing's sarcoma 6 4 2 -
Neuroblastomat 7 1 2(1H 4
Osteosarcoma 8 1 3 (1) 4
Rhabdomyosarcoma 2 2 - -
Retinoblastoma 2 1 1 -
Other 11 6 3 2
- - - -
. .
TOTAL 36 1% 11 (2) 10

* Patients entered into the protocol for "optimal
nutritional support of patients with cancer metastatic
to or from bone." Four patients refused entry.
t There is overlap but not identity in the series
in Table 4 and this table for neuroblastoma. Here
eligibility for the protocol counted.
$ The number in parentheses indicates crossover to a
malnourished slate.
8 Incidence of malnutrition: 15/40 (37.5%).

quent and appeared rapidly, when not ETIOLOGYOF .MALNUTRITION

averted by IVH, in 2 of 5 patients presumably
well nourished. This suggested the existence There is only one cause of protein energy
of marginal malnutrition. malnutrition, namely inadequate intake for
caloric demands. T h e physiological conse-
INCIDENCE OF MALNUTRITION quences of such inadequate intake are im-
portant and need to be understood to deal
Even when only overt malnutrition is con- with the problem of rehabilitation of the mal-
sidered, it is far more frequent than w e are nourished patient. However, for patient
prone to admit. I n an ongoing cooperative management a simple initial conceptualiza-
randomized clinical trial of adjuvant hyper- tion must be made. Inadequate intake can
alimentation there are t w o sets of patients. occur from many and obvious reasons. First,
In the first set, newly diagnosed patients, who lack of appetite. This is very frequent. We all
were planned to have abdominal or pelvic know the inadequacies of dietary recall
tumors were enrolled. The incidence of mal- history. But a history of poor eating in a child
nutrition among such patients was 7/40 or who is overtly malnourished requires .little
17.5% (Table 2). The second set includes pa- detailed documentation. Secondly, psycho-
tients who have metastatic disease to or from logical factors play a role. Learned food aver-
bone. Among 40 patients meeting the entry sion through associations between food and
criteria, the incidence of overt malnutrition chemotherapy can be experimentally demon-
was 15/40 or 37.5% (Table 3). In addition, strated.2 Thirdly, there is malabsorption. This
among 11 patients managed by conventional is frequently iatrogenic, from radiotherapys
feeding 2 became malnourished in the course o r chemotherapy, such as methotre~ate.'~
of therapy. T h e effect of methotrexate on the intestinal
The malnutrition is not uniform among all lining is early and profound.10 The almost in-
types of cancer. Table 3 also shows a break- discriminate use of high dose methotrexate
down among the diagnoses of patients that makes this a major problem. But malnutri-
were enrolled in the study. It can be seen that tion itself can cause malabsorption, so that the
Ewing's sarcoma is a major setting for clinical problem is frequently a vicious cycle. Fourth-
malnutrition while in osteosarcoma malnutri- ly, there may be excess nutrient loss-steroid-
tion is not as common. induced diabetes, severe renal protein loss, or
I t can be concluded from these limited data persistent nausea and vomiting. Finally, there
that overt malnutrition is not rare among is no doubt that tumors cause major increases
children with cancer and that it is not random. in caloric demands. It is therefore clear then
It is higher among patients with advanced dis- that predictors of marginal malnutrition can
ease, even though not limited to them, and it be stated even when it is as yet not objectively
is higher among certain diagnoses. diagnosable: In children with cancer, seem-
No. 5 MALNUTRITION
I N CHILDREN
W I T H CA uan Eys 2033

ingly well nourished, marginal malnutrition is tained a positive skin test during chemother-
likely to be present when there is: apy and concomitant hyperalimentation.
Common childhood illnesses have an ex-
1) Inadequate dietary intake of long tremely high mortality rate among children
standing. with protein-energy malnutrition."." P ) u w n o -
2) Therapy, already ongoing, leading to cystis cariiiii infection was frequent in neonates
prolonged anorexia and/or malab- with protein energy malnutrition who had
sorption without parenteral interven- neither cancer nor cancer c h e m ~ t h e r a p yI.t~
tion. is quite likely that immune suppression in
3) Certain diagnoses, such as Ewing's children with cancer, and its concomitant
sarcoma or neuroblastoma, where ac- complications, is as often as not nutritional
tive and/or progressive disease is pres- rather than chemotherapy or disease induced.
ent, and there is no parenteral nutri-
tion intervention. M I C K O N U T R I ENT DEFIc I E N C Y
CONSEQUENCES
OF MALNUTRITION Inadequate intake is the cause of protein-
calorie malnutrition. I t is reasonable to predict
It could be and frequently is argued that
that there could be imbalanced intake to cause
malnutrition is not in itself bad. If and when micronutrient deficiency. T h e r e are few data
therapy is successful, nutritional state im- describing such a state. Protein deficiency prr
proves. Animal data even seem to suggest that so results in a seemingly zinc-deficient state in
starvation is therapeutically antineoplastic. anirnals.l8 Many children clearly show zinc
Yet there are obvious and highly undesirable
deficiency signs. Furthermore, overt zinc
side effects of malnutrition in the child with
deficiency is a recognized complication of pro-
active cancer. longed hyperalimentation.' There is no direct
First of all, the most obvious yet least objec-
relationship known between cancer and zinc
tive reason for nutritional support is that a
deficiency, but it can become a complication
child who is malnourished is listless and feels of the nutritional management.
poorly. T h e parents are highly anxious. T h a t More importantly, however, it must be con-
alone ought to be enough argument.
tinually remembered that a child with cancer
However, secondly, the tolerance to chemo-
is still a child. Iron deficiency seen so often in
therapy is less in the malnourished state. Most otherwise healthy children is equally possible
pediatric and adult phase I1 chemothera- i n children with cancer, if not more so because
peutic protocols have written in a distinction
of our diagnostic phlebotomies. Vitamin K
between good and poor risk patients. Those deficiency occurs because of the frequent pro-
criteria usually are highly correlated with, if longed antibiotic therapy and relatively fat-
not equivalent to, well and poorly nourished. free diets.
Such impressions are now objectively and There is as yet no clear correlation between
prospectively examined in patients who have outcome a n d micronutrient deficiencies.
metastatic disease through a randomized trial There are beginning to be hints, however.
of adjuvant hyperalimentation. Early data al- There is now evidence in animals that in-
ready are suggestive. In the patients men- creased vitamin E protects against aclriamycin
tioned in Table 1, dose adjustments in therapy cardiot~xicity.'~ This is o n e clear instance
were most frequent in patients at time of mal- where one specific nutrient has a bearing on
nutrition. chemotherapeutic tolerance.
Thirdly, there is a strong relationship be-
tween malnutrition i m m ~ n i t y It
. ~involves in EFFECTOF NUTRITIONAL
SUPPORT
animal models a decreased defense against
bacterial infections, including impaired leuko- As in severe protein-calorie malnutrition in
cyte activity, decreased antibody formation, other settings, overt malnutrition demands
decreased cell mediated immunity, and de- vigorous therapy. Parenteral hyperalimenta-
generating tissue integrity.I2 Chronic protein tion is a safe and effective approach, even in
deprivation affects especially the T cell sys- the setting of clinically active cancer. Table 4
tem. Immunocompetence in general is asso- shows the experience with hyperalimentation
ciated with improved therapeutic response in our department over the last 2 years. Since
and longer survival in rats.2*6Copeland3 noted hyperalimentation of less than 10 days' dura-
that a response to chemotherapy was seen only tion is ineffective, all patients are treated for
in those adult patients who developed or re- at least that length of time. We are, there-
 2034 'Ma) Supplement 1979
CANCER
TABLE
4. Intravenous Hyperalimentation
M . D. Anderson Hospital
Year Year
1976-1977 1977-1978
Patients 20 35
Catheter insertions 37 90
Catheter source
sepsis* 3% 3%
Catheter related
sepsist 10% 10%
~~~~~ ~ ~ ~
* Demonstrated infected catheter. (Sepsis is calculated
per insertion.)
t A positive blood culture, during intrarenous hyper- outcome is not adversely affected in osteo-
alimentation, of known etiology, and proven lack o f sarcoma or Ewing's sarcoma.
catheter vegetations.
fore, summarizing in excess of 1,300 pa-
tient-days on IVH during this period. Com-
plications from IVH are few. Infection is low
when meticulously guarded against. Two pa-
tients have been o n IVH for 180 and 110+
days. Neither patient has had catheter sepsis,
although 1 had major myelosuppressive
chemotherapy, while the other had two bone
marrow transplants with chemotherapeutic
marrow ablation before both. During that
period there were 2 weeks of total bone mar-
row aplasia.
Intravenous hyperalimentation can be ef-
fective even in the presence of intensive
chemotherapy. Among the patients men-
tioned in Table 1, the 3 o n IVH because of
malnutrition became well nourished by all
criteria. Serum albumin went from an average
of 3.5 (2.8; 3.7; 3.9) g/dl to a level of 4.2 (4.1;
4.1; 4.4) g/dl by the third month. Weight/
height ratios started at <5%; <5%, and 10th
percentile to change to around the 25th per-
centile in all 3 patients.
These patients received IVH 3 days prior to
the start of chemotherapy. A total of 10 days at
full strength IVH was administered. In all pa-
tients cytoxan (80 mg/kg I V , followed by vin-
cristine (0.03 mg/kg IV) was administered o n
day 1 and day 2. Trifluorothymine deoxy-
riboside and papaverine were given (both 4 5
mg/kg IV) on days 3 a n d 4." T h e cycle was
repeated monthly. T h i s combination is
severely myelosuppressive. Four episodes of
infection occurred in 48 treatment courses.
One of these was a fatal, cytomegalovirus
pneumonia in a malnourished child, who was
initially managed by oral feeding but de-
veloped malnutrition a n d died before re-
habilitation could be accomplished.
Val. 43
Hyperalimentation did not adversely affect
tumor growth. Two patients o n hyperalimen-
tation had a second look operation and both
Total not only had their neuroblastoma arrested
but maturation had occurred to ganglio-
55 neuroma. All other patients responded objec-
127
tively to therapy.
Therapy tolerance and outcome in other
tumors cannot be objectively gauged at this
time because the prospective study of hyper-
alimentation is ongoing. T h e r e is no doubt
that subjective tolerance is improved and that
NUTRITION TO TUMOR
AS A N ADJUVANT
SPECIFIC THERAPY
If nutrition is safe and effective in overtly
malnourished patients, and if tumor growth
is not adversely affected, it is a logical exten-
sion to use nutrition as an adjuvant therapy.
Again the experience in the patients men-
tioned in Table 1 shows that this approach is
feasible. N o crossover has occurred to mal-
nourished from well nourished in patients o n
IVH, even though there undoubtedly were
marginally malnourished children in that
group. All 3 children were in or around the
25th percentile of weight for height, and
therefore were not robust.
There tnust also be patients who have excel-
lent nutritional reserve and who will respond
t o chemotherapy promptly, making it unlikely
that marginal malnutrition exists or even will
develop. Introducing hyperalimentation as a
routine adjuvant makes it mandatory that its
efficacy and usefulness must be proven in the
marginally malnourished. This puts a high
premium on the diagnosis of such patients in
the setting of pediatric oncology.
Until such time, the information seen in
Table 3, that more than 1 of 3 patients with
metastatic disease to or from bone is overtly
malnourished, and the fact that significant sal-
vage is demonstrated in children previously
treated, suggest that while good outcome is
possible, malnutrition is a major complicating
factor. I t is in this group that vigorous hyper-
alimentation seems indicated, if indeed the
prospective clinical trial further indicates the
beneficial trend so far seen.
CONCLUSION
Malnutrition is frequently a cause of death.
As chemotherapy has become routine, bleed-
No. 5 MALNUTRITION
IN CHILDREN
WITH CA
ing and infection are given as the most fre-
quent ultimate causes of death in childhood
cancer. But only very recently a standard text-
book of pathology reminded us that “The
most common way in which malignancy leads
to death is cachexia: the development of pro-
gressive weakness, weight loss and wasting.”I6
T h e simple data presented ought to be suf-
ficient to show that malnutrition is still a
problem, that marginal malnutrition exists,
even if it is not definable, and that overt mal-
nutrition can be treated and also prevented.
There is a historical study ongoing to define
the true magnitude of incidence of malnutri-
tion using a larger denominator.
This malnutrition ought to be dealt with.
Any approach to nutritional management will
have a major impact on the type of care we
give and the outcome we can expect. It is going
to be vital that data are gathered in orderly
REFERENCES
1. Arakawa, T., Tamura, T.. Igarshi, Y., Suzuki. M.,
and Sandstead. H. H.: Zinc deficiency in two infants dur-
ing total parenteral alimentation lor diarrhea. A m . ] . Clin.
Nutr. 29: 197-204. 1976.
2. Bernstein, 1. L.: Learned taste aversions in children
receiving Chemotherapy. Scicnct 200: 1302- 1303, 1978.
3. Bosworth, J. L., Ghossen, N. A.. Books, T. L.:
Delayed hypersensitivity in patients treated by cura-
tive radiotherapy. Cnnrvr 36:353-358, 1975.
4. Cliandra, R. K., and Newberne. P. M.: Nutrition.
Immunity and Infections: Mechanisms of Interaction.
N e w York, Plenum Press, 1977.
5. Copeland. E. M., MacFadyen, B. V.. Lanzotti. V.J.,
and Dudrick. S. J.: Nutritional care of the cancer pa-
tient. f i t Cancer Patient Care at M. D. Anderson Hospital
and Tumor Institute, R. L. Clark, and C. D. Howe. Eds.
Chicago, Year Book Medical Publishers, 1976; pp. 607-
628.
6. Donaldson, S. S.: Nutritional consequences of radio-
therapy. ( h i c u r Rec. 37:2407-24 13. 1977.
7. Dutz, W.. Post. C . . Vessal, K., and Kohout. E.:
Endemic infantile Piirumoryclis cnrinii infection. 111
Symposium on PnPurnorvh rcrrirrii Intection. .J. B. Rob-
bins, V. T. d e Vita, Jr., and W. Dutz, Eds. N u f . Cnricur/iu/.
hf<Jfl(Jfl.43:31 -38. 1976.
8. Eilber, F. R., and Morton, D. L.: Impaired iminuno-
logic reactivity and recurrence following cancer surgery.
Cunrcr 25:363-367. 1970.
9. Gordon. J. E., Jansen, A. A. J., and Ascoli, W.:
Measles in rural Guateniala. J. Pvdialr. 66:779-786,
1965.
* van Eys 2035
fashion while introducing attention to nutri-
tional support of our children with cancer.
Research questions abound: nutrition and im-
munity need further definitions, objective
diagnosis of marginal malnutrition is desper-
ately needed, evaluation of the effect of
changes in selected nutrient levels is clearly
required (after all methotrexate is a n anti-
folate and therefore nutritional therapy);
design and evaluation of optimal nutritional
support protocols is a formidable task; reset-
ting of chemotherapy tolerance in face of ade-
quate nutritional state requires relearning of
our optimal treatment designs, modes of
delivery of nutritional support must be im-
proved upon; and first and last evaluation of
long-term nutritional support of patients with
cancer-distorted requirements, and defining
such cancer induced nutritional needs, is
clearly an unsolved problem.
10. Green, H. L.: T h e effects of malnutrition and can-
cer therapy agents on small bowel. I n Nutrition and Can-
cer, J. van Eys,B. J. Nichols. and M. Seelig, Eds. Spectrum
Press, 1979.
1 1 . Helson, L.. Helson, C., Peterson, R. F.. and Das.
S. K.: A rationale for :he treatment of metastatic neuro-
blastonia./. N ~ ICanr.
. Ins!. 57:727-729, 1976.
12. Lantham. M. C.: Nutrition and infection in na-
tional development. S r i r n r r 188:56 1-565, 1975.
13. Madanat, F., Wang. Y. M.. and Ali, M. K.: Vitamin
E and Adriamycin cardiac toxicity in rabbits. Pror. A A C R
and ASCO 19623, 1978 (Abstract).
14. Morley. P.: Severe measles in the tropics. B r . .ifd,
J. i:297-301, 1969.
15. Perez, C.. Sutow, W. W.. Wang, Y. M., and Herson,
J.: Evaluation of overall toxicity of high dose metho-
trexate regimens. ,Men. Prdirrtr. Oncol. (In press).
16. Robbins. S. L.: Textbook of’ Pathology. Philadel-
phia, W. B. Saunders. 1962; p. 45.
17. Sutow. W. W.: General aspects of childhood can-
cer. / n Clinical Pediatric Oncology, W. W. Sutow, T. J .
Vietti. and D. J. Fernbach. Eds. Second edition. S:. I.ouis,
C:. V . Mosby Co., 1977; pp. 1-5.
18. van Campen, D., and House, W.A,: Et’lect o1.a low
protein diet on retention of an oral dose 01. “Zn and on
tissue concentration of zinc, iron and copper i n ra1s.J.
h‘ttlr. 104:84-90, 1974.
19. Wolff, J . A.. D’Angio, G., Hartmann, J., Krivit, W..
and Newton, W. A.. Jr.: Long-term evaluation ol. single
versus multiple courses of actinomycin D therapy of
Wilms’ tumor. N. Engl. J . Mud. 290:84-86, 1974.