R E V I E W
Symptom Clusters in Cancer Patients
and Their Relation to EGFR Ligand
Modulation of the Circadian Axis
Tyvin A. Rich, MD, FACR
C
ancer patients suffer from a variety of
physical, affective, and cognitive symptoms caused either directly or indirectly
by the cancer itself or its treatment. In
this review, we focus on a common symptom
cluster of fatigue, appetite loss, and sleep disruption,1 the causes of which are multidimensional.
Although there may be disagreement as to what
constitutes a symptom cluster, available data justify lumping together these particular symptoms
for the purposes of our discussion.
The ‘Sickness Behavior’ Model
and Symptom Clustering
Models for symptom production based on molecular mechanisms are well illustrated by the “sickness
behavior” model, which hypothesizes that tumors,
in conjunction with a host response, produce proinflammatory cytokines such as interleukin (IL)-1
and IL-6 and tumor necrosis factor-alpha (TNFα).2,3 In this model, observed behaviors, such as decreased activity, appetite loss, and somnolence, can
be induced in laboratory animals with the administration of lipopolysaccharide. Likewise, excessive
production of pro-inflammatory cytokines in humans is thought to result in signaling cascades that
upregulate brain cytokine levels, induce fever, and
disrupt the hypothalamic-pituitary-adrenal (HPA)
axis that contributes to symptom production.4
Clinical evidence for this hypothesis comes from
the observation that elevated serum levels of IL-6
are associated with “B symptoms” (typically defined
as fever and malaise) in patients with lymphomas
Manuscript submitted August 11, 2006;
accepted September 9, 2006.
Correspondence to: Tyvin A. Rich, MD, FACR, Department
of Radiation Oncology, University of Virginia Health Sciences
Center, PO Box 800383, Charlottesville, VA 22901; telephone: (434) 924-5191; e-mail: [email protected]
J Support Oncol 2007;5:167–174
VOLUME 5, NUMBER 4
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Abstract Recent studies in chronobiology and the neurosciences have
led to rapid growth in our understanding of the molecular biology of the
human timekeeping apparatus and the neuroanatomic sites involved in
signaling between the “master clock” in the hypothalamus and other
parts of the brain. The circadian axis comprises a central clock mechanism and a downstream network of hypothalamic relay stations that
modulate arousal, feeding, and sleeping behavior. Communication between the clock and these hypothalamic signaling centers is mediated,
in part, by diffusible substances that include ligands of the epidermal
growth factor receptor (EGFR). Preclinical studies reveal that EGFR ligands
such as transforming growth factor-alpha (TGF-α) inhibit hypothalamic
signaling of rhythmic behavior; clinical observations show that elevated
levels of TGF-α are associated with fatigue, flattened circadian rhythms,
and loss of appetite in patients with metastatic colorectal cancer. These
data support the hypothesis that a symptom cluster of fatigue, appetite
loss, and sleep disruption commonly seen in cancer patients may be related to EGFR ligands, released either by the cancer itself or by the host in
response to the stress of cancer, and suggest that further examination of
their role in the production of symptom clustering is warranted.
(including Hodgkin’s disease), acute myelogenous
leukemia, myelodysplastic syndromes, or pancreatic
cancer who have a poor prognosis.5–8 Further support comes from the observations of mental changes
such as neurologic fatigue clustered with a loss of
motivation, lack of energy, and depression in cancer patients treated with interferon alfa (IFN-α)8,9
and/or IL-29,10 in which administration of IFN-α
was associated with increased serum levels of IL-6
and IL-10, an anti-inflammatory cytokine produced
in response to the production of pro-inflammatory
cytokines.10 Other researchers have shown positive
correlations between elevated levels of IL-6 or vascular endothelial growth factor (VEGF, thought to
signal through the IL-6 pathway) and altered psychosocial, quality-of-life, and depression indices in
untreated cancer patients.11,12
The continued attraction of the pro-inflammatory cytokine hypothesis stems from the similarity
Dr. Rich is Professor of
Radiation Oncology,
Department of Radiation
Oncology, University of
Virginia Health Sciences
Center, Charlottesville.
www.SupportiveOncology.net
167
Symptom Clusters and Their Relation to EGFR Ligand Modulation of the Circadian Axis
Rhythmic clock gene
and clock-controlled
gene activity in core
and shell SCN neurons
and astrocytes
Neurotransmitters:
VIP, GRP, GABA, VP
Diffusable molecules:
TGF-α, PK2, CLC
OUTPUT
INPUT
Retina
Figure 1
Hypothalamus
Basal forebrain
Ventral thalamus
Midline thalamus
Suprachiasmatic Nucleus: “The Central Clock”
This schematic shows the major components of the central circadian axis.
Light impinging on the retina acts as a dominant entraining condition on
the clock. The central clock produces rhythmic output signals that communicate to areas mainly in the hypothalamus to produce circadian regulation of physiology and behavior.
Abbreviations: CLC = cardiotrophin-like cytokine; GABA = gamma-aminobutyric acid; GRP = gastrin-releasing peptide; PK2 = prokineticin-2; SCN =
suprachiasmatic nucleus; TGF-α = transforming growth factor-alpha; VIP =
vasoactive intestinal peptide; VP = vasopressin
of the laboratory findings with the clinical symptoms displayed
in cancer patients. Although the precise target(s) in the brain
in the sickness behavior model are not well understood, this
hypothesis is novel and is the subject of ongoing investigation.
The clustering of symptoms in cancer patients also suggests
that a shared biologic mechanism exists for their production
and that there may be a commonly shared neuroanatomic target within the central nervous system. In this review, a new
hypothesis for symptom production is discussed that is based
on targeted signaling by members of the epidermal growth factor receptor (EGFR) family that disrupt hypothalamic circadian modulation. The background for this idea is provided by
studies emerging from the fields of chronobiology13–15 and the
neurosciences,16–19 two disciplines that have seen a recent explosion in our understanding of the central molecular clock20
and its rhythmic output to downstream signaling networks
within the hypothalamus that modulate circadian behavior.
Data will be reviewed here supporting the continued investigation of symptom clusters in cancer patients that link disruption in rhythmic behavior of the 24-hour rest/activity pattern
(as related to fatigue), feeding, and sleep to tumor-produced
growth factors that appear to inhibit the hypothalamic relay
stations involved in circadian signaling.
The Circadian Axis and Chronobiologic
Regulation in Humans
The central circadian system, described here in simplified
form, has three major functional components. The first compo-
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nents are signaling inputs, the most dominant of which is the
timing of exposure to ambient light perceived by specialized
sensors in the eye, that result in neurophysiologic changes in
the central clock within the hypothalamus (Figure 1).21 The
clock is also affected by the hormone melatonin, which participates in a feedback loop from the pineal gland to strengthen
the darkness period of the circadian cycle.21–23 The light-dark
cycle is considered the dominant input into the central oscillating apparatus that acts to entrain an imprecise clock that
must be repeatedly reset.24 In addition, the central clock receives resetting input signals from other areas of the brain, as
well as external signals. This input provides functional plasticity, allowing an organism to adapt to anticipated changes in the
environment due, for example, to a shift in time zone with jet
travel or shifting lighting conditions as the seasons progress.
The second component of the circadian timing system
is the central oscillator (represented by the clock in Figure
1) that produces electrophysiologic signals that arise from
paired populations of neurons in the suprachiasmatic nuclei
(SCN).25–27 Specialized “core and shell” neurons in the SCN
produce an entrainable approximate 24-hour rhythm that
is expressed in all mammals.28 Rhythmic output is produced
even in the absence of environmental cues (such as the conditions prevailing in deep cave isolation studies) that result
in “free-running” behavior.29,30 Another unique feature of the
central oscillator’s output is constant periodicity over a wide
temperature range.24
The third component of the central circadian timing system is composed mainly of afferent nerve fiber groups projecting from the SCN to the hypothalamus and represents the
output network.18 By relaying excitatory or inhibitory signals
to other centers in the hypothalamus, these connections comprise an output network that modulates the synchronized,
rhythmic physiology and behavior of the organism. Activation
or inhibition of hypothalamic centers facilitates specific behaviors that are associated with rhythmic patterns of arousal
and sleep, core body temperature, and appetite. Signals from
these hypothalamic neuroendocrine centers regulate the secretion of reproductive, stress-axis, and physiology-regulating
hormones, and by their effects on the parasympathetic and
sympathetic autonomic centers in the brainstem, they help
maintain physiologic balance.31
LESSONS LEARNED FROM SCN ABLATION STUDIES
To better understand how the clock influences physiology
and behavior, researchers have performed SCN ablation studies in an attempt to correlate loss of clock function with physiologic and behavioral changes in laboratory animals.32–34 SCN
ablation causes permanent loss of rhythmic rest/activity, core
body temperature, feeding, and sleep behavior patterns.33,35
Experimentally induced loss of circadian rhythms can be reversed by implanting embryonic SCN tissue into the area of
the host’s ablated SCN or using encapsulated SCN preparations that prevent axonal connections but allow diffusion of
secreted factors and partial restoration of clock function.15 It
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Rich
is this part of the recent story of circadian rhythm research
that may be the key to understanding how symptom clusters
in patients are related to circadian signaling. A thorough investigation of candidate factors secreted from the hamster
SCN has identified three SCN peptides that are ligands of the
EGFR: epidermal growth factor (EGF), transforming growth
factor-alpha (TGF-α), and neuregulin-1 (NRG-1).13,15 Another diffusible factor produced in the SCN that may signal
hypothalamic nuclei is prokineticin-2 (PK2),36–39 a molecule
closely related to the VEGF found predominately in endocrine
tissues. In addition to the ligands of the EGFR and VEGF family, the last factor identified in the SCN is the cardiotrophinlike cytokine (Clc), a neuropeptide related to IL-6 that signals
through the gp130 receptor.40 The functional activity of these
ligands on circadian signaling in the hypothalamus has been
evaluated using an intracerebroventricular infusion technique
that delivers them through a microcatheter inserted directly
into the third ventricle of the brain. These infusion studies
show that all five peptides (EGF, TGF-α, NRG-1, PK2, and
Clc) reversibly inhibit circadian body temperature rhythms,
eliminate running-wheel activity, decrease feeding, and deregulate 24-hour sleep patterns.
DOWNSTREAM HYPOTHALAMIC MODULATION
OF CIRCADIAN RHYTHMS
One concept put forth based on observations from ablative lesions created downstream from the SCN in the hypothalamus is that hypothalamic modulation of circadian time
structure18 is an important function of these hypothalamic
relay stations. There are important functional consequences
of downstream SCN signal interruption at the sites of secondary and tertiary signal relay stations (Figure 2).18 For example,
lesions to the subparaventricular zone (SPZ), at either the
dorsal or ventral nuclei, can diminish circadian rhythms in
rest/activity, sleep, and core body temperature, depending
upon which of these two nuclei are damaged.41 Other laboratory investigations show that selective destruction of the
dorsal medial nucleus (DMH) in the hypothalamus interrupts
rhythmic feeding behavior.18,19 One important consequence
of hypothalamic modulation is the ability to adapt to predominately diurnal or nocturnal activity despite the signal activity
of the SCN clock always being highest during the light phase.
This modulation of circadian rhythmicity can also sculpt behavior in optimal ways that can confer survival advantages on
the organism. Clinical evidence supporting this argument is
also provided by the finding of functional impairment similar
to the behavioral and functional losses created by hypothalamic nuclei ablation studies described in the altered sleep/
wake patterns of patients recovering from viral illness.42 The
neuropathic behavior in these patients correlated with histologic destruction of areas of the anterior hypothalamus near
the junction of the brainstem and the forebrain in the SPZ
and DMH.17 These damaged sites coincide with the downstream circadian sleep/wake centers of the anterior hypothalamus and not the SCN.
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Other consequences of modulation of circadian rhythms by
hypothalamic signaling downstream from the central oscillator is that circadian signaling can be subject to inputs from the
brain’s visceral, limbic, and cortical systems. Rhythmic signaling
can be modulated, amplified, or inhibited at these hypothalamic
behavioral relay centers. This design feature theoretically allows
for signal inputs from sources outside the brain, for example, by
neurally active peptides (cytokines or growth factors) associated
with infection, inflammation, cancer, and other disease states.
Under these conditions, we postulate that the peripheral production of neurally active peptides can modify the SCN/hypothalamic signaling axis with potential consequences on physiologic and behavioral drives such as arousal, feeding, and sleep.
The production of the type of symptom clusters seen in cancer
patients could thus be explained by inhibition of hypothalamic
signaling pathways by products of the tumor itself.
Does Circadian Rhythm Dysregulation
Occur in Cancer Patients?
The master clock mechanism illustrated in Figures 1 and 2
serves as the coordinator of physiologic and behavioral circadian periodicity through the generation of rhythmic signaling
in the SCN and downstream modulation at paraventricular
hypothalamic nuclei. However, a more complete picture of
the cellular timing mechanism shows that the circadian system is composed of multiple peripheral oscillators, in addition
to the central timing mechanism.26,43 This concept has grown
out of an understanding of circadian rhythms based on the
existence of a molecular autoregulatory transcription-translation feedback loop involving at least 15 “clock” genes.44 The
core oscillator genes and downstream clock-controlled genes
are found in all tissues; indeed, DNA microarray analysis has
shown that transcription and translation of 10%–30% of the
human genome undergo circadian oscillations.24,45
Based on these findings, the circadian axis can be thought
of as operating in a hierarchical fashion under the direction
of a master clock that signals peripheral oscillators to synchronize and coordinate cellular function.21,25 The peripheral
clocks are considered to be under the control of the central
clock, functioning as local modulators of gene expression in
each organ (eg, liver, heart, kidneys). This ubiquitous timekeeping mechanism tailors local gene-expression patterns differently in each tissue and organ while using the same set of
clock genes that function in the SCN.
THE ROLE OF ‘CLOCK GENES’
Molecular clock gene studies show that several mutations
are associated with changes in wakefulness, sleep, and adaptive behavior.46–50 The clock gene PER1 (homolog of Drosophila
period 1 gene) has been well studied; polymorphisms of this
gene are associated with advanced and delayed sleep-phase
syndromes referred to as “morning lark” and “night owl” behavioral patterns. More details of these conditions are reviewed
elsewhere.24,51 The relevance of these findings to cancer patients is unknown, since there are no known associated cancer
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169
Symptom Clusters and Their Relation to EGFR Ligand Modulation of the Circadian Axis
A
B
Thermoregulation
PVHm
CRH
Corticosteroid
secretion
TGF-α
dSPZ
MPO
DMH
vSPZ
VMH
DMH
SCN
SCN
ARC
Leptin
Ghrelin
C
D
Wakefulness, feeding
Orexin
MCH
Sleep
PVHd
Leptin
Melatonin
secretion
LHA
GABA
TGF-α
Glutamate
TRH
VLPO
vSPZ
DMH
SCN
Ghrelin
Figure 2
SCN
ARC
Leptin
Hypothalamic Modulation of Circadian Behavior
Signals emanating from the suprachiasmatic nucleus (SCN) are modulated in the hypothalamic nuclei, resulting in the modification, amplification, or inhibition of circadian behavior and physiology: (A) thermoregulation; (B) cortisol secretion; (C) wakefulness, appetite; (D) melatonin secretion. One mechanism
that theoretically can contribute to altered behavior is the inhibitory effects produced by transforming growth factor-alpha (TGF-α) on the epidermal growth
factor receptor (EGFR) at the level of the ventral nuclei of the subparaventricular zone (vSPZ).
Abbreviations: ARC = arcuate nucleus of the hypothalamus; CRH = corticotropin-releasing hormone; DMH = dorsomedial hypothalamus; dSPZ = dorsal nuclei of
the subparaventricular zone; GABA = gamma-aminobutyric acid; LHA = lateral hypothalamic area; MCH = melanin-concentrating hormone; MPO = medial preoptic
nucleus of the hypothalamus; PVHd = paraventricular nucleus of the hypothalamus, descending division; PVHm = paraventricular nucleus of the hypothalamus,
magnocellular division; TRH = thyrotropin-releasing hormone; VLPO = ventrolateral preoptic area of the hypothalamus; VMH = dorsomedial hypothalamus.
Adapted, with permission, from Saper et al18
syndromes in patients with these types of molecular clock disorders. Perhaps of greater importance regarding cancer research is
the recent discovery that the core clock gene PER2 (homolog
of the murine gene Per2) is a tumor suppressor gene described
in a Per2 knockout system that results in a malignant phenotype
in experimental animals.52,53 This finding is not surprising, given
that the clock genes in peripheral tissues are closely tied to cellcycle checkpoints, cellular proliferation, and apoptosis.54,55
The precise roles these clock genes play in regard to cancer
are still largely unknown, but one aspect that has been elucidat-
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ed is the relationship between the clock genes and proliferation
described in oral mucosa studies from human volunteers.56–58 In
these studies, serial biopsies of the oral mucosa showed significant correlations with clock-gene expression and progression
through the cell cycle, as well as expression levels of cell-cycle
checkpoint proteins (eg, cyclin A and E). Other molecular studies indicate a critical role in circadian control of the cell-cycle
checkpoint at the transition from the G2 phase to the M phase.
The consequences of disruption of circadian signaling at the
level of the core clock or clock-controlled genes involved with
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proliferation and apoptosis could be important to cancer induction and promotion and are areas under active investigation.
A
ACTIGRAM
B
AUTOCORRELATION
ALTERED CIRCADIAN RHYTHMS IN CANCER PATIENTS
In addition to the new knowledge describing the molecular
actions of the central and peripheral clocks, there is an abundant older literature regarding rhythmic physiology and behavior in cancer patients. Both laboratory and clinical studies show
that a variety of circadian parameters may be altered in patients
with cancer, including peripheral blood cells; bone marrow proliferation; hormone levels (typically, serum melatonin and cortisol levels); and miscellaneous parameters such as body temperature, urinary volume, and levels of tumor markers.59
In general, early-stage cancer patients exhibit little or no
measurable differences in circadian rhythms compared with
those in normal populations or people with diseases other
than cancer. Patients with advanced primary cancers or metastatic disease, however, show disrupted chemical, physiologic,
and behavioral rhythms, including amplitude dampening,
phase shifts, and/or period changes with ultradian rhythms, or
rhythms that occur more frequently than every 24 hours.60 Although disrupted rhythmic physiologic and behavior patterns
are observed in cancer populations, the question can be raised
of whether circadian disruption is a marker for advanced disease or whether there is a mechanistic relationship between
circadian disruption and cancer progression and prognosis.
CORTISOL RHYTHMS
Approaches to answer this question have involved measurement of two circadian parameters in cancer patients that
have mechanistic underpinnings. One method is the evaluation of cortisol rhythms as measured in either saliva or serum; one report showed that a significant correlation exists
between dampened circadian rhythm of salivary cortisol levels
and prognosis in patients with metastatic breast cancer.61 A
flatter cortisol rhythm was associated with the presence of
distant metastasis versus local/regional disease, and this
finding remained significant for survival even when other
prognostic factors were controlled for in the study.
This correlation was further strengthened by a second study
that compared cortisol rhythms in age-matched healthy controls with those in cancer patients.62 These data suggest that
cancer patients with high “allostatic loads” from stress and disease have a disrupted HPA axis, which, in turn, results in poor
outcomes because of detrimental effects on natural killer cells
and lymphocytes in combating cancer.63,64 The cortisol rhythm
data suggest that disruption to the HPA axis, a mechanistic
centerpiece for the sickness behavior model, produces psychologic, neurologic, and immunologic alterations that might directly contribute to poor outcomes in cancer patients.
REST/ACTIVITY PATTERNS
Other rhythmic behavior data can be obtained in cancer
patients with the assessment of 24-hour rest/activity patterns
(an example of an actigram is shown in Figure 3) obtained
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Robust rhythm
Dampened rhythm
Figure 3
Rhythmic Behavior Data
(A) Actigram recorded with a wrist-worn accelerometer for 2 consecutive
days. (B) Autocorrelation: analysis of the type of data obtained in panel A
showing different circadian rest/activity patterns that can be labeled either
“robust” or “dampened.”
with a wrist-worn accelerometer. This device detects circadian
rhythms and is a well-accepted research tool in human sleep
and circadian biology.65–69 Prospective measurement of rest/activity patterns by wrist actigraphy has been correlated with poor
outcomes in patients with metastatic colorectal cancer, where
dampened motor-activity rhythms were associated with significant levels of fatigue and appetite loss and poor survival.66
In other studies where rest/activity patterns were measured
prior to treatment, actigraphy showed that disruption of these
patterns was independently associated with poor performance
status and quality of life and revealed a flattening of circadian
rest/activity patterns in patients receiving chemotherapy.68,70
Other actigraphy studies have confirmed a high degree of correlation of disturbed rest/activity patterns with quality-of-life
indices and symptom clusters of fatigue, change in appetite,
and sleep disruption.71
These studies provide further evidence that disruption of
rhythmic physiologic processes contributes to poor prognosis
in cancer patients. A molecular mechanism to explain these
findings has not been available until recently. It is discussed in
the following section.
Symptom Production in Cancer Patients
and the EGFR Ligand Hypothesis
The importance of the EGFR in the cancer process and
EGFR inhibition as a therapeutic intervention is a well-established success story in the management of several solid human
tumors.72 EGFR signaling occurs through the dimerization of a
pair of members of the EGFR family that communicate extra-
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Symptom Clusters and Their Relation to EGFR Ligand Modulation of the Circadian Axis
Table 1
Correlation of Circadian Rhythms With Clinical Indices, Pro-Inflammatory Cytokines,
and EGFR Ligand Levels in 80 Patients With Metastatic Colorectal Cancer
ASSESSMENT OF INDIVIDUAL PATIENT
CIRCADIAN RHYTHM BY ACTIGRAPHY
Robust rhythma (autocorrelation > 0.47)
(n = 40)
Dampened rhythm (autocorrelation < 0.35)
(n = 40)
CORTISOL RATIO
(SLOPE)
SERUM LEVEL
OF TGF-α
SERUM LEVEL
OF IL-6
CLINICAL INDICES
1.72 (steep)
Low
Low
Less fatigue and appetite loss
1.60 (flat)
High
High
More fatigue and appetite loss
Differences in cortisol ratio, serum levels of TGF-α and IL-6, and clinical indices are statistically significant.
Abbreviations: EGFR = epidermal growth factor receptor; IL-6 = interleukin-6; TGF-α = transforming growth factor-alpha
Adapted from Rich et al83
a
cellular information into intracellular signals that are involved
with pathways controlling proliferation, apoptosis, angiogenesis, survival, adhesion, and differentiation.72–74 Therapeutic
intervention based on targeted inhibition of this pathway with
monoclonal antibodies or tyrosine kinase inhibitors has improved the outcomes of patients with cancer of the head and
neck, breast, lungs, colon, rectum, and pancreas.75–79
One area of the EFGR story that has been relatively underdeveloped is a fuller understanding of the role the EGFR
ligands themselves may play in cancer prognosis. For example,
there is evidence that patients with lung, pancreatic, colorectal, or breast cancer whose tumors overexpress EGFR and who
have high levels of the EGFR ligand TGF-α have a particularly poor prognosis.80–82 One reason for their worse prognosis
may be related to the increased autoregulatory mechanism of
self stimulation by locally produced EGFR ligands like TGF-α
where these growth-signaling pathways produce agonistic effects on growth and angiogenesis, as has been demonstrated in
patients with pancreatic and non-small cell lung cancer.81,82
DISRUPTION OF CIRCADIAN
RHYTHMS BY EGFR LIGANDS
An additional reason for the poor prognosis in these patients
may be related to the inhibition of hypothalamic modulation of
circadian rhythms by TGF-α, which, in turn, accounts for the
symptom clustering of fatigue, appetite loss, and sleep disruption
observed in cancer patients. The studies with intracerebroventricular infusions of TGF-α described earlier in this review show
it is an SCN locomotor inhibitor and targets EGFR-positive
cells at the level of the circadian relay stations in the SPZ.13,14
Although TGF-α has been localized in the adjacent glial cells
and not in the neurons in the SCN, that does not necessarily
negate its participation as a “diffusible signaling” substance in
the SCN that can disrupt circadian rhythmicity when infused
into the third ventricle. Our hypothesis is that patients with
elevated serum levels of TGF-α would be expected to show loss
of motor activity (ie, fatigue), have poor appetite, and display
other symptoms, such as sleep disruption, associated with interference of hypothalamic circadian signaling.
This hypothesis has been examined in a retrospective clinical study of 80 patients with metastatic colorectal cancer who
were originally evaluated for chronomodulated chemotherapy
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and assessed prior to treatment with a battery of quality-of-life
studies and measurement of 24-hour rest/activity patterns by
wrist actigraphy.83 As shown in Table 1,83 a significant correlation was found in these patients between dampened circadian
rhythm (low r24), poor quality-of-life scores, high serum levels
of the pro-inflammatory cytokines IL-6, TNF-α, and TGF-α
and flattened cortisol rhythms. These data support the EGFRligand hypothesis and are currently being validated with new
correlative studies.
CAN EGFR INHIBITION REVERSE THESE EFFECTS?
As a means of cross-validating the hypothesis that EGFR
ligands produce symptom clusters in cancer patients, it would
be logical to ask if there are data from therapeutic interventions with EGFR inhibitors that are associated with symptom
changes in cancer patients. One might expect that EGFR inhibition would lead to improvement in those symptoms that are
related to TGF-α blockade of the circadian signals emanating
from the hypothalamus. Studies of the tyrosine kinase inhibitor
gefitinib (Iressa) in metastatic non-small cell lung cancer have
shown a rapid improvement in quality-of-life indices that is
four-fold higher than the objective tumor response in the same
patients.84,85 Although some of this effect on quality of life could
be explained by a direct antitumor effect, mentation and appetite rapidly improved in these patients, suggesting an effect
of gefitinib independent of tumor response. The mechanism for
this effect is not entirely understood, but the findings are consistent with the EGFR hypothesis that some human cancers produce neurally active peptides that produce symptom clusters.
The Future: Targeted Therapy for
Symptom Management?
Our understanding of the mechanisms by which rhythmic
physiologic processes and behavior are regulated on the molecular level has improved with the discovery of the details of
cellular timekeeping and the activity of a family of core and
clock-controlled genes involved with metabolism, the cell
cycle, proliferation, and apoptosis. Recent discoveries in chronobiology and the neurosciences regarding the location and
mechanisms of circadian signaling downstream from the SCN
in the hypothalamus have also shed new light on how rhythmic behavior of the organism is regulated. The EGFR ligand
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hypothesis overlaps areas of behavioral research, symptom research, and cancer biology in new and testable ways.
LIMITATIONS OF THE EGFR HYPOTHESIS
One of the shortcomings of the EGFR ligand hypothesis is
that there are several other neurally active molecules that might
contribute to symptom clustering in cancer patients besides the
members of the EGFR family. First, there are at least four SCN
locomotor inhibitors that have been identified in the brain infusion model, and although two of these are also members of the
EGFR family, such as TGF-α, two others also have connections
to cancer since one of them is PK2 (a form of VEGF) and the
other is Clc, which is related to the proinflammatory cytokine
IL-6. This last finding overlaps with our clinical observations in
metastatic colorectal cancer patients, in whom altered circadian rhythms correlated with higher symptom levels and poorer
survival in those patients with elevated levels of IL-6. In theory,
cross-signaling could occur between these ligands’ families,
since IL-6 is a pleiotropic cytokine that has been associated with
proinflammatory conditions, poor survival, and the production
of sleep dysfunction and other symptoms.86,87 Additional correlative studies with multiple biologic markers for the sickness
behavior model and the EGFR ligands are therefore indicated.
The fields of symptom management and chronobiology are
driven today with discoveries regarding the timing of processes
involving molecular biologic events regulating intracellular and
intercellular signaling. The studies discussed here suggest that
symptoms in cancer patients can be produced by signaling molecules produced by either the tumor or the host. The pro-inflammatory and growth factor hypotheses each share similarities, since
each relies on the production of neurally active molecules that interfere with brain signaling. Application of this knowledge might
someday translate into new mechanistically based therapeutic interventions for humans suffering from cancer-related symptoms.
CIRCADIAN-BASED PROGNOSTIC MARKERS
One approach, especially for the assessment of the circadian
axis, would be to measure rhythmic chemical and activity levels in cancer patients to identify those patients with dampened
rhythms, since it appears that this would segregate patients into
unique groups with different prognoses. This approach is now
being done with actigraphy but could soon include other noninvasive or minimally invasive means of monitoring a person’s
biorhythms that would allow quantification of behaviors that
may be useful for fine-tuning host performance status. Circadian-based prognostic markers could also be used for the testing
of new hypotheses, with individualized cancer therapy having a
specific and targeted biologic basis.
Acknowledgments: The author wishes to acknowledge Mr.
John E. Heilmann for his support of this research.
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