C h a p t e r 7
Neoplasia
145
be due, in part, to a dysregulation of iron metabolism,
leading to a functional iron deficiency.
37
Cancer-related anemia is associated with reduced
treatment effectiveness, increased mortality, increased
transfusion requirements, and reduced performance
and quality of life. Hypoxia, a characteristic feature of
advanced solid tumors, has been recognized as a critical
factor in promoting tumor resistance to radiotherapy
and some chemotherapeutic agents.
Cancer-related anemia is often treated with iron
supplementation and recombinant human erythropoi-
etin (rHuEPO, epoetin alfa).
37
Since iron deficiency
may result in failure to respond to erythropoietin, it
has been suggested that iron parameters be measured
before initiation of erythropoietin therapy. When treat-
ment with supplemental iron is indicated, it has been
suggested that it be given intravenously, since oral iron
has been shown to be largely ineffective in persons with
cancer.
37
Anorexia and Cachexia
Many cancers are associated with weight loss and wasting
of body fat and muscle tissue, accompanied by profound
weakness, anorexia, and anemia. This wasting syndrome
is often referred to as the
cancer anorexia–cachexia syn-
drome
.
38–40
It is a common manifestation of most solid
tumors with the exception of breast cancer. The condi-
tion is more common in children and elderly persons
and becomes more pronounced as the disease progresses.
Persons with cancer cachexia also respond less well to
chemotherapy and are more prone to toxic side effects.
The cause of the cancer anorexia–cachexia syn-
drome is probably multifactorial, resulting from a
persistent inflammatory response in conjunction with
production of specific cytokines and catabolic factors
by the tumor. Although anorexia, reduced food intake,
and abnormalities of taste are common in people
with cancer and often are accentuated by treatment
methods, the extent of weight loss and protein wast-
ing cannot be explained in terms of diminished food
intake alone. There also is a disparity between the size
of the tumor and the severity of cachexia, which sup-
ports the existence of other mediators in the develop-
ment of cachexia. It has been demonstrated that tumor
necrosis factor (TNF)-
α
and other cytokines including
interleukin-1 (IL-1) and IL-6 can produce the wast-
ing syndrome in experimental animals.
3
High serum
levels of these cytokines have been observed in per-
sons with cancer, and their levels appear to correlate
with progress of the tumor. Tumor necrosis factor-
α
,
secreted primarily by macrophages in response to
tumor cell growth or gram-negative bacterial infec-
tions, was the first identified cytokine associated with
cachexia and wasting. It causes anorexia by suppressing
satiety centers in the hypothalamus and increasing the
synthesis of lipoprotein lipase, an enzyme that facili-
tates the release of fatty acids from lipoproteins so that
they can be used by tissues. IL-1 and IL-6 share many
of the features of TNF-
α
in terms of the ability to initi-
ate cachexia.
Fatigue and Sleep Disorders
Fatigue and sleep disturbances are two of the side effects
most frequently experienced by persons with cancer.
41–45
Cancer-related fatigue is characterized by feelings of
tiredness, weakness, and lack of energy and is distinct
from the normal tiredness experienced by healthy indi-
viduals in that it is not relieved by rest or sleep. It occurs
both as a consequence of the cancer itself and as a side
effect of cancer treatment. Cancer-related fatigue may
be an early symptom of malignant disease and has been
reported by as many as 40% of patients at the time of
diagnosis.
42
Furthermore, the symptom often remains
for months or even years after treatment.
The cause of cancer-related fatigue is largely unknown
but is probably multifactorial and involves the dysregu-
lation of several interrelated physiologic, biochemical,
and psychological systems. The basic mechanisms of
fatigue have been broadly categorized into two compo-
nents: peripheral and central. Peripheral fatigue, which
has its origin in the neuromuscular junction and muscles,
results from the inability of the peripheral neuromus-
cular apparatus to perform a task in response to cen-
tral stimulation. Mechanisms implicated in peripheral
fatigue include a lack of adenosine triphosphate (ATP)
and the buildup of metabolic by-products such as lactic
acid. Central fatigue arises in the central nervous system
(CNS) and is often described as the difficulty in initiat-
ing or maintaining voluntary activities. One hypothesis
proposed to explain cancer-related fatigue is that cancer
and cancer treatments result in dysregulation of brain
serotonin (5-HT) levels or function. There is also evi-
dence that proinflammatory cytokines, such as TNF-
α
,
can influence 5-HT metabolism.
Paraneoplastic Syndromes
In addition to signs and symptoms at the sites of primary
and metastatic disease, cancer can produce manifesta-
tions in sites that are not directly affected by the disease.
Such manifestations are collectively referred to as
para-
neoplastic syndromes.
46,47
Some of these manifestations
are caused by the elaboration of hormones by cancer
cells, and others result from the production of circulat-
ing factors that produce hematopoietic, neurologic, and
dermatologic syndromes (Table 7-3). These syndromes
are most commonly associated with lung, breast, and
hematologic malignancies.
2
A variety of peptide hormones are produced by both
benign and malignant tumors. Although not normally
expressed, the biochemical pathways for the synthesis and
release of peptide hormones are present in most cells.
47
The three most common endocrine syndromes associated
with cancer are the syndrome of inappropriate antidi-
uretic hormone (ADH) secretion (see Chapter 8), Cushing
syndrome due to ectopic adrenocorticotropic hormone
(ACTH) production (see Chapter 32), and hypercalcemia
(see Chapter 8). Hypercalcemia also can be caused by
osteolytic processes induced by cancer such as multiple
myeloma or bony metastases from other cancers.
Some paraneoplastic syndromes are associated with
the production of circulating mediators that produce
