Atanu Kumar Pati A Arti Parganiha2007

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Alterations of the Characteristics of the Circadian Rest-Activity Rhythm of

Cancer In-Patients
Atanu Kumar Pati a; Arti Parganiha ab; Anjana Kar a; Rakesh Soni a; Sushmita Roy c; Vivek Choudhary c
a
School of Life Sciences, Pt. Ravishankar Shukla University, Raipur, India b INSERM U776, Rythmes
Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France c Regional Cancer Center, Pt. Jawaharlal
Nehru Medical College, Raipur, India
Online Publication Date: 01 November 2007
To cite this Article Pati, Atanu Kumar, Parganiha, Arti, Kar, Anjana, Soni, Rakesh, Roy, Sushmita and Choudhary,
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International,24:6,1179 — 1197
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Chronobiology International, 24(6): 1179–1197, (2007)
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DOI: 10.1080/07420520701800868
ALTERATIONS OF THE CHARACTERISTICS OF THE CIRCADIAN

REST-ACTIVITY RHYTHM OF CANCER IN-PATIENTS
Atanu Kumar Pati,1 Arti Parganiha,1,2 Anjana Kar,1 Rakesh Soni,1

Sushmita Roy,3 and Vivek Choudhary3
1
School of Life Sciences, Pt. Ravishankar Shukla University, Raipur, India
2
Downloaded By: [INFLIBNET India Order] At: 09:51 7 September 2009
INSERM U776, Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France
3
Regional Cancer Center, Pt. Jawaharlal Nehru Medical College, Raipur, India
The aim of the present study was to evaluate the characteristics of the circadian rest-
activity rhythm of cancer patients. Thirty-one in-patients, consisting of 19 males and
12 females, were randomly selected from the Regional Cancer Center, Pandit
Jawaharlal Nehru Medical College, Raipur, India. The rest-activity rhythm was
studied non-invasively by wrist actigraphy, and compared with 35 age-matched appar-
ently healthy subjects (22 males and 13 females). All subjects wore an Actiwatch (AW64,
Mini Mitter Co. Inc., USA) for at least 4– 7 consecutive days. Fifteen-second epoch
length was selected for gathering actigraphy data. In addition, several sleep par-
ameters, such as time in bed, assumed sleep, actual sleep time, actual wake time,
sleep efficiency, sleep latency, sleep bouts, wake bouts, and fragmentation index,
were also recorded. Data were analyzed using several statistical techniques, such as
cosinor rhythmometry, spectral analysis, ANOVA, Duncan’s multiple-range test, and
t-test. Dichotomy index (I , O) and autocorrelation coefficient (r24) were also com-
puted. The results validated a statistically significant circadian rhythm in rest-activity
with a prominent period of 24 h for most cancer patients and control subjects.
Results of this study further revealed that cancer patients do experience a drastic
alteration in the circadian rest-activity rhythm parameters. Both the dichotomy
index and r24 declined in the group of cancer patients. The occurrence of the peak
(acrophase, Ø) of the rest-activity rhythm was earlier ( p , 0.001) in cancer patients
than age- and gender-matched control subjects. Results of sleep parameters revealed
that cancer patients spent longer time in bed, had longer assumed and actual sleep
durations, and a greater number of sleep and wake bouts compared to control subjects.
Further, nap frequency, total nap duration, average nap, and total nap duration per
1 h awake span were statistically significantly higher in cancer patients than control
subjects. In conclusion, the results of the present study document the disruption of
the circadian rhythm in rest-activity of cancer in-patients, with a dampening of
amplitude, lowering of mean level of activity, and phase advancement. These
Submitted December 15, 2006, Returned for revision January 9, 2007, Accepted October 25,
2007
Address correspondence to Dr. Atanu Kumar Pati, Ph.D., F.N.A.Sc.School of Life Sciences, Pt.
Ravishankar Shukla University, Raipur 492 010, India. E-mail: akpati19@gmail.com or akpati19@
hotmail.com
1179
1180 A. K. Pati et al.
alterations of the circadian rhythm characteristics could be attributed to disease,

irrespective of variability due to gender, sites of cancer, and timings of therapies.
These results might help in designing patient-specific chronotherapeutic protocols.
(Author correspondence: akpati19@gmail.com or akpati19@hotmail.com)
Keywords Rest-activity pattern, Circadian rhythm, Head and neck cancer,

Reproductive organ cancer, Dichotomy index
INTRODUCTION
The extent of the toxicity and efficacy of a number of anticancer drugs/
agents applied in experimental animal models vary with the time of their
administration (Lévi, 2001, 2006). These phenomena have been attributed
to the 24 h rhythms of both the host and tumor (Filipski et al., 2002).
The clinical relevance of these findings has been amply validated in

cancer patients (Eriguchi et al., 2003; Kobayashi et al., 2002). However,
inter-individual variations in the characteristics of circadian rhythms
among human cancer patients make it extremely difficult to devise a gen-
eralized therapeutic strategy. This is a reason why patient-specific therapy
is considered more useful (Mormont & Lévi, 2003). Furthermore, a
suitable marker rhythm is necessary to ensure effective outcomes of the
chronotherapeutic approach (Mormont et al., 2002).
Currently, in clinical chrono-oncology, wrist-actigraphy is used to vali-
date the circadian rest-activity rhythm of patients (Chevalier et al., 2003;
Levin et al., 2005; Mormont & Waterhouse, 2002). Moreover, this
rhythm has been previously investigated as a potential suitable marker
of the internal circadian time organization (Chevalier et al., 2003;
Mormont & Waterhouse, 2002). Pati et al. (2006) recently reported that
the circadian rest-activity rhythm dampens in patients suffering from
head and neck cancer. Although this information was the first from the
Indian subcontinent, it was based on a small sample of patients. The ration-
ale of the present study was to gather data on a greater number of cancer
patients from India and to test the hypothesis of the dampening of
circadian rest-activity rhythm in cancer.
PATIENTS AND METHODS

Biographical and Clinical Characteristics of Subjects
Thirty-one cancer in-patients, 19 males and 12 females, were selected
randomly from the Regional Cancer Centre, Pt. J.N. Medical College,
Raipur, India. Thirteen patients were suffering from cancer in the
region of head and neck, eight in the reproductive organs, and the remain-
ing ten in other organs. The performance status (PS) of the patients ranged
Circadian Rest-Activity Rhythm of Cancer Patients 1181
from fully active (0) to completely disabled (4), according to the criteria of
the Eastern Cooperative Oncology Group (ECOG; Oken et al., 1982). The
initial evaluation included blood pressure and temperature measure-
ments. During the period of this study, the in-patients received either
intravenous chemotherapy (n ¼ 20), radiotherapy (n ¼ 7), or both
(n ¼ 4) in the morning (n ¼ 27) or afternoon (n ¼ 4). Chemotherapy con-
sisted of a combination of two or three of the following medications:
5-fluorouracil (500– 600 mg/m2), cisplatin (40– 60 mg/m2), gemcitabine
(1000 mg/m2), peclitaxel (180 – 200 mg/m2), doxorubicin (50– 60 mg/
m2), and carboplatin (450– 600 mg/m2). Cobalt 60 (1.33 Mev) was used
as the energy for radiotherapy. In addition, several other medications
and blood transfusions were prescribed to minimize treatment side
effects, such as nausea, vomiting, diarrhea, and anemia. The biographical
and clinical characteristics of the in-patients and apparently healthy sub-

jects, those who did not self-report any disease, are summarized in
Table 1. This design and conduct of the study complied with the ethical
standards of Chronobiology International (Touitou et al., 2006).
Assessment of the Characteristics of Circadian Rest-Activity

Rhythm
The circadian rest-activity rhythm was monitored non-invasively by
wrist actigraphy (Actiwatch, Model AW64, Mini Mitter Co., Inc.) worn
TABLE 1 Biographical and Clinical Characteristics of Cancer In-patients and Control Subjects
Attribute Description
Number of patients (M/F) 31 (19/12)

Age (yrs), median/range 43/17–75
Site of cancer Head and neck (n ¼ 13), Reproductive organs
(n ¼ 8), or Other organs (n ¼ 10)
Specific site of cancer Alveolus (3), Buccal mucosa (4), Supra glottis (1),
Esophagus (1), Larynx (2), Tongue (1), Lung (1),
Cervix (3), Ovary (2), Penis (1), Vagina (1), Testis
(1), Intestine (1), Liver (1), Rectum (2), Soft tis-
sue (1), Thigh (3), Blood (2)
Metastasis cases 7
Cancer stage 2 or 3 or 4
ECOG performance status 4- PS (3), 3- PS (4), 2- PS (5), 1- PS (8), 0- PS (11)
Treatment
Chemotherapy/radiotherapy/both 20/7/4
Drugs used for chemotherapy 5-Fluorouracil, Cisplatin, Gemcitabine, Peclitaxel,
Doxorubicin, and Carboplatin.
Source of radiation Cobalt 60
Symptomatic drugs Granisetron, Paracitamol, Filgrastim
Cycles of chemotherapy/radiotherapy 1 (15), 2 (6), 3 (4), 6 (3)/20 (3)
Number of control subjects (M/F) 35 (22/13)
Age (yrs), median/range 35/19–61
on the non-dominant arm over a continuous four day span, when the
in-patients were admitted to receive either chemotherapy, radiotherapy,
or both. Pre- and post-treatment wrist activity data could not be collected
because of the following reasons: only seriously ill patients are admitted to
the in-patient ward without prior notice; most of the patients come from
distant and remote areas, are illiterate, and fail to furnish valid postal
addresses; and most of them do not have phone/email facilities at their
residences. Thirty-five apparently healthy subjects, 22 males and 13
females, also wore the Actiwatch for at least 4–7 consecutive days on
their non-dominant arm and formed the control group. Both patients
and healthy subjects gave a written informed consent.
The actigraph consists of an accelerometer (a piezoelectric sensor
device capable of converting movement into measurable electrical
signals), a filter that excludes external vibrations by selectively registering

values only in the 1.0 to 2.5 Hz range, a programmable memory into which
it stores the resulting values, and a user interface program that allows for
its configuration. Data were collected at 15 sec epochs. The duration of
monitoring was in compliance with the recommendations of the American
Academy of Sleep Medicine (1997) and an American Academy of Sleep
Medicine Report (Littner et al., 2003).
Study of Sleep Parameters

The following sleep parameters were also studied in both groups as
determined by the application of the Actiware-Sleep Software (Mini
Mitter Co., Inc.) to the data:
. Time in Bed (TIB). The amount of time spent in bed, derived as the differ-
ence between the get up time and bedtime.
. Assumed Sleep (AS). The difference in time between the Sleep End and
Sleep Start times. This parameter was calculated automatically using
values derived from the sleep scoring algorithm of the Actiware-Sleep
software.
. Actual Sleep Time (AST). The amount of time between Sleep Start and
Sleep End, scored as sleep according to the Actiware-Sleep algorithm.
It is determined by the summation of the number of epochs that do
not exceed the sensitivity threshold and multiplying that value by the
epoch length in min. AST is expressed in h and min.
. Actual Wake Time (AWT). The amount of time between Sleep Start and
Sleep End, which is scored as wake according to the Actiware-Sleep soft-
ware. It is determined by the summation of the number of epochs that
exceed the sensitivity threshold and multiplying that value by the
epoch length in min. AWT is expressed in h and min.
. Sleep Efficiency (SE). An index of the amount of time in bed actually spent
sleeping. It is determined by the division of the actual sleep time by time
in bed and multiplying the result by 100.
. Sleep Latency (SL). The period of time required for sleep onset after retir-
ing to bed. Sleep latency is the period between Bed Time and Sleep
Start.
. Sleep Bout (SB). The number of continuous blocks of sleep calculated
between Sleep Start and Sleep End.
. Wake Bout (WB). A measure of the intervening waking periods between
Sleep Start and Sleep End. It is indicative of fitful sleep if short sleep
bouts alternate with short waking bouts.
. Fragmentation Index (FI). An index of restlessness. It indicates the extent
to which sleep is disturbed in an individual.
In addition, either the patients or their attendant recorded the bedtime,

wake-up time, and meal timings in a diary on daily basis. The time to
bed was verified from the data obtained from the Actiware-Sleep software.
The apparently healthy subjects recorded the above parameters them-
selves. The data on sleep parameters were transferred to a Microsoft
Excel worksheet for further analyses.
In addition, the frequency of naps (NF), the total time spent napping
(TN), the average nap length (AN), and the total time spent napping per
1 h awake (TN/A) time were determined by Actiware-Sleep software. A
nap was defined as suspected sleep periods of less than 1 h during the
awake-span.
Statistical Analyses
The circadian rhythm characteristics, such as average of the rhythmic
function (mesor, M: rhythm-adjusted 24-h mean), amplitude (A, one-half
of the difference between the highest and the lowest value of the 24 h
cosine approximation fit to the data), and peak or acrophase (Ø, timing
of the highest value of the rhythmic function) were estimated from log-
transformed data (Nelson et al., 1979) at two different fixed windows
(i.e., t ¼ 24 h and t ¼12 h). The additional 12 h period was especially
selected because bimodality in the activity pattern was discerned in the per-
iodograms/actograms of most of the subjects. Harmonic means were cal-
culated for M, A, and Ø obtained at both windows. The prominent
period (t) of the studied variable was determined by Power Spectrum
Analysis technique (De Prins et al., 1986), which is applicable to time
series with or without missing data. Autocorrelation analyses, which do
not presume the shape of a cyclic function, were also applied to derive
the autocorrelation coefficient at t ¼ 24 h (i.e., r24) to obtain another
measure of the regularity of the activity pattern over the 24 h. The
dichotomy index, I , O, differences in activity distribution between the

daily activity and rest spans were also computed. The dichotomy index
I , O is the percentage of the 1 min activity values measured while the
patient is in bed that is inferior to the median value when the patient is
out of bed. The value of this index can vary between 0% and 100%. In
the case of a marked circadian rhythm with complete rest at night and
high activity during daytime, I , O reaches 100%. Other statistical tech-
niques, such as descriptive statistics, ANOVA followed by Duncan’s mul-
tiple-range test, and t-test were also used when pertinent (COSTAT,
CoHort Software, Version 4.02, #1990).
RESULTS
Rest-Activity Rhythm
Figure 1 shows the actograms of the rest-activity patterns in cancer in-
patients and control subjects. The apparently healthy male and female sub-
jects displayed a distinct and regular day-night pattern in wrist activity;
more activity was displayed during the day than night (see Figure 1B
and 1D). However, in the male and female cancer in-patients this distinc-
tion and regularity was less marked (see Figure 1A and 1C). The cancer in-
patients also showed daytime napping. The level and intensity of activity
were higher in the male and female control subjects than male and
female cancer patients.
Rhythm Detection
A statistically significant circadian rhythm (t ¼ 24 h) in rest-activity was
documented in all control subjects and cancer in-patients, irrespective of
the sites of the cancer. Most of the subjects also exhibited statistically signifi-
cant 12 h rhythmicity in rest-activity. The harmonic means of the mesors,
amplitudes, and acrophases obtained separately for the 24 and 12 h
periods were computed and are reported in Table 2. Figure 2 illustrates
the best-fitting cosine curves in selected cancer patients (n ¼ 18) and
control subjects (n ¼ 10). Spectral analyses revealed the period of the
rest-activity rhythm to be exactly 24 h in most control subjects and
cancer in-patients. However, in four cancer patients and one control
subject, frequency multiplication of the rest-activity rhythm was witnessed,
with a period length of 12 or 6 h. Figure 3 shows illustrative examples of
circadian and non-circadian prominent periods in the rest-activity
rhythm of four cancer patients (see Figure 3A – 3D) and two control sub-
jects (Figure 3E and 3F). In these examples, several smaller peaks were
observed in cancer patients, whereas in control subjects, only a secondary
peak was observed at 12 h. Although control subjects had a prominent
FIGURE 1 Illustrative examples of double-plotted rest-activity profile (actogram) in cancer in-patients

(A and C) and apparently healthy subjects (B and D). Abscissa depicts clock hour. Each row represents
two 24 h spans (i.e., for a given day and the following day). The height of the black marks in each row
indicates the level of activity (counts in relative unit) for the corresponding time in the abscissa. Acto-
grams of cancer patients reveal marked activity in the nighttime.
1185
TABLE 2 Summary of the Characteristics of Circadian Rest-Activity Rhythm of Cancer In-patients and Control Subjects. Rhythm Parameters were Computed at Fixed
Windows with t ¼ 24 h or t ¼ 12 h. The Harmonic Means of Each Parameter Obtained at t ¼ 24 h and t ¼ 12 h were also Calculated
Cancer patients Control subjects Cancer vs.

control: t
value ( p
Variable Mean + SE (n) Median (range) Mean + SE (n) Median (range) value)
Rhythm parameters at t ¼ 24 h
24 h average, M 00.98 + 00.05 (31) 00.99 (00.17, 01.67) 01.64 + 00.03 (35) 01.66 (01.34, 01.94) 11.48 (0.001)
Amplitude, A 00.48 + 00.03 (31) 00.47 (00.09, 00.91) 00.92 + 00.02 (35) 00.95 (00.60, 01.19) 11.33 (0.001)
Acrophase, Ø in h 13.81 + 00.26 (31) 13.90 (10.10, 17.50) 15.29 + 00.19 (35) 15.00 (13.70, 18.50) 04.65 (0.001)
1186
Rhythm parameters at t ¼ 12 h
24 h average, M 00.98 + 00.05 (31) 01.00 (00.17, 01.67) 01.66 + 00.03 (35) 01.69 (01.37, 02.00) 11.77 (0.001)
Amplitude, A 00.29 + 00.02 (31) 00.30 (00.04, 00.53) 00.53 + 00.02 (35) 00.51 (00.31, 00.84) 08.32 (0.001)
Acrophase, Ø in h 08.40 + 00.12 (31) 08.50 (07.00, 09.70) 09.04 + 00.14 (35) 08.90 (07.60, 11.20) 03.45 (0.001)
20.40 + 00.12 (31) 20.50 (19.00, 21.70) 21.04 + 00.14 (35) 20.90 (19.60, 23.20)
Rhythm parameters (harmonic mean)
24-h average, M 00.98 + 00.05 (31) 00.99 (00.17, 01.67) 01.65 + 00.03 (35) 01.68 (01.36, 01.97) 11.69 (0.001)
Amplitude, A 00.35 + 00.02 (31) 00.35 (00.06, 00.59) 00.66 + 00.02 (35) 00.65 (00.42, 00.89) 11.36 (0.001)
Acrophase, Ø in h 10.41 + 00.14 (31) 10.30 (09.00, 11.90) 11.35 + 00.16 (35) 11.10 (09.90, 13.40) 04.56 (0.001)
FIGURE 2 Representative examples of cosine-fitted curve in cancer in-patients and control subjects
based on harmonic means of mesors, amplitudes, and acrophases obtained independently at fixed win-
dows with periods equal to 24 h and 12 h (A: male control, B: male patient, C: female control, D: female
patient). Same scale has been used in each plot. The following cosine function was used in the single
cosinor method: Yti ¼ MþA cos (vti þ Ø) þ ei, where Yti ¼ the value of the fitted cosine function at
time ti. M ¼ mesor (rhythm-adjusted mean), which is equal to the arithmetic mean when measure-
ments are taken at equidistant time intervals. A ¼ amplitude (one-half the difference between the high-
est and the lowest value of the rhythmic function). v ¼ angular frequency (degrees per unit time, with
3608 representing a complete cycle). t ¼ time when measurements are taken. Ø ¼ peak (acrophase:
timing of the highest value with reference to local midnight). ei ¼ uncontrollable random error
assumed to be independent normal and deviates with means zero and common variance. Figures indi-
cate all cancer in-patients and control subjects exhibited a significant circadian rhythm in rest-activity;
however, the amplitude considerably dampened in most cancer in-patients, irrespective of gender, as
compared to their respective apparently healthy counterparts. The bimodality in rest-activity rhythm
also appeared to be dampened in cancer patients.
period of 24 h, most of them exhibited a secondary peak at 12 h. This

bimodality in the rest-activity rhythm was drastically suppressed among
the cancer patients.
Circadian 24 h Average (Mesor)

The averages of the mesors for each group obtained at the fixed
windows of 24 h, 12 h, and their harmonic means are shown in Table 2.
The results of cosinor rhythmometry indicated inter-individual differences
in the level of 24-h average activity in cancer in-patients and control sub-
jects. Results showed a statistically significant ( p , 0.001) difference in
the harmonic means of the mesors of the activity rhythm between cancer
in-patients and control subjects, independent of gender (see Figure 4A).
This difference was also statistically significantly validated when activity
FIGURE 3 Illustrative examples of prominent periods of the 24 h rest-activity rhythm in two female
cancer in-patients (A and B), two male cancer in-patients (C and D), and two-control subjects (E: female,
F: male). One control subject and four cancer in-patients exhibited a period less than 24 h.
count, obtained at the fixed window with t ¼ 24 h, was expressed as

average activity per 15 min (see Figure 4B).
Circadian Amplitude
Variation in the inter-individual as well as group circadian amplitudes
of the rest-activity rhythm was observed in both groups. The harmonic
means of the amplitude of the rest-activity rhythm in the cancer in-patients
were significantly lower ( p , 0.001) than those of the control subjects, irre-
spective of gender (see Figure 4C).
Circadian Peak (Acrophase)

The harmonic means of the circadian acrophase of the rest-activity
rhythm of the subjects were localized mostly in the morning hours. A stat-
istically significant ( p , 0.001) difference was observed for the average
timing of the peaks between the two groups. The acrophase of the rest-
activity rhythm occurred earlier, by about 1 h, in the cancer in-patients
than the controls (see Figure 4D).
FIGURE 4 24 h average based on harmonic means (A), average level of activity per 15 min intervals (B),
amplitude based on harmonic means (C), and acrophse based on harmonic means (D) of the circadian
rest-activity rhythm of control subjects and cancer in-patients, mean dichotomy index, I , O (E), and
autocorrelation coefficient, r24 (F). For all the mentioned rhythm parameters, statistically significant
( p , 0.001) differences were noticed between the cancer in-patients and control subjects, except r24.
Dichotomy Index (I < O)

The mean dichotomy index was drastically lower in the cancer in-
patients (female cancer patients vs. female controls, p , 0.001; male
cancer patients vs. male controls, p , 0.001; all cancer patients vs. all con-
trols, p , 0.001) compared with the control subjects (see Figure 4E).
Autocorrelation Coefficient (r24)

The autocorrelation coefficients at t ¼ 24 h, the r24, were computed
for each cancer patient and control subject. In each subject, the r24
value was statistically significant. However, statistically significant differ-
ences were not obtained when the averages of r24 values of the cancer
patients and control subjects were compared as a group (see Figure 4F).
Nonetheless, the group mean r24 was lower in the cancer in-patients
than control subjects (Figure 4F).
Peak (Acrophase) Map

The harmonic means of the peaks (acrophase) of the rest-activity circa-
dian rhythm in 35 control subjects (22 males and 13 females) and 31 cancer
in-patients (19 males and 12 females) are plotted in Figure 5A and 5B. The
maps reveal inter-individual variability in the acrophase of the 24 h rest-
activity rhythm among both the cancer in-patients and apparently
healthy control subjects.
Sleep and Nap Parameters

Table 3 depicts the means and standard errors of TIB, AS, AST, AWT,
SE, SL, SB, WB, FI, NF, TN, AN, and TN/A of the cancer in-patients and
control subjects. Cancer patients spent a longer time in bed and had longer
assumed and actual sleep durations than control subjects. The average
FIGURE 5 Acrophase map showing the timings (harmonic mean) of occurrences in the circadian rest-
activity rhythm of individual control subjects (A) and cancer in-patients (B).
duration of the sleep and wake bouts was significantly longer in the
cancer in-patients than controls. In addition, nap frequency, total nap
duration, average nap, and total nap duration per 1 h awake-time were
statistically significantly higher in cancer patients than control subjects
(see Table 3).
DISCUSSION
A noticeable difference between the rest-activity circadian pattern of
healthy subjects and cancer in-patients was observed. The normal day-
night variability in cancer patients was impaired. Comparable impairment
of the normal day-night pattern in the activity has been documented in
patients suffering from breast cancer (Roscoe et al., 2002), metastatic color-
ectal cancer (Chevalier et al., 2003; Mormont & Waterhouse, 2002), lung
cancer (Levin et al., 2005), and head and neck cancer (Pati et al., 2006).
Healthy subjects exhibit a high amplitude 24 h rest-activity rhythm charac-
terized by high level activity during the daytime (waking) hours and very
low to zero-level activity during the night (rest). The onset and offset of
activity timings of the healthy subjects can be well differentiated and are
consistent from one day to the next. However, in the cancer in-patients,
this distinction was less marked. These observations corroborate with the
findings of several earlier studies (Chevalier et al., 2003; Levin et al.,
2005; Mormont & Waterhouse, 2002; Pati et al., 2006).
The present results show that all of the cancer patients and control sub-
jects exhibited a statistically significant circadian rest-activity rhythm.
These observations are in full agreement with previous reports that docu-
mented statistically significant 24 h rhythmicity in rest-activity, plasma con-
centrations of melatonin, 6-a-sulfatoxymelatonin, cortisol, and lymphocyte
count in apparently healthy subjects and cancer patients (Chevalier et al.,
2003; Minors et al., 1996; Mormont et al., 2000, 2002; Pati et al., 2006).
Levin et al. (2005) reported a disruption of the 24 h sleep-activity
pattern in patients suffering from advanced non-small-cell lung cancer.
Disruption of the sleep-activity pattern does not necessarily mean the
absence of a statistically significant circadian rhythm. A consistent
rhythm in serum cortisol level has also been reported in patients with
advanced gastrointestinal carcinomas (Raida et al., 2002). Therefore,
the rest-activity appears to be a robust circadian variable, as all cancer
patients and control subjects exhibited a statistically significant rhythmic
pattern.
It is well known that the 24 h pattern of the rest-activity in humans is
shaped more like a square than a sinusoidal waveform; hence, the
cosinor method is less meaningful in the present context. Therefore, we
applied three additional analyses to properly validate our findings:
TABLE 3 Means (+1 SE) of Time in Bed (TIB), Assumed Sleep (AS), Actual Sleep Time (AST), Actual Wake Time (AWT), Sleep Efficiency (SE),
Sleep Latency (SL), Sleep Bouts (SB), Wake Bouts (WB), Fragmentation Index (FI), Nap Frequency (NF), Total Nap (TN), Average Nap (AN), and
Total Nap Per 1 h Awake (TN/A) of Cancer Patients (n ¼ 31) and Control Subjects (n ¼ 35)
Variable (unit) Control subjects Median (range) Cancer patients Median (range)
TIB (h) 7.41 + 0.16 7.10 (6.06, 9.81) 8.13 + 0.22b 8.14 (5.50, 10.22)
AS (h) 6.55 + 0.18 6.41 (4.46, 9.17) 7.22 + 0.25a 7.31 (4.02, 9.61)
AST (h) 5.62 + 0.14 5.46 (4.01, 7.54) 6.18 + 0.23a 6.17 (3.23, 9.27)
AWT (h) 1.00 + 0.06 0.86 (0.48, 1.70) 1.04 + 0.09ns 0.99 (0.33, 2.04)
SE (%) 76.05 + 1.23 76.93 (63.16, 91.40) 75.62 + 1.74ns 77.10 (55.13, 90.50)
1192
SL (min) 29.42 + 4.60 21.28 (3.00, 109.50) 30.02 + 4.14ns 24.00 (1.00, 82.50)
SB (count) 29.47 + 1.52 26.86 (18.00, 60.25) 41.82 + 1.99c 40.25 (18.67, 62.00)
WB (count) 30.86 + 2.09 26.60 (17.73, 79.00) 41.12 + 1.98c 39.75 (18.00, 61.25)
FI (%) 28.96 + 1.68 32.06 (4.55, 47.31) 24.99 + 2.86ns 18.17 (6.30, 66.63)
NF (count) 3.81 + 0.44 3.67 (0.14, 8.75) 16.58 + 1.42c 17.00 (2.5, 33.5)
TN (sec) 1848.35 + 216.47 1826.25 (42.86, 43.00) 7959.09 + 711.75c 7811.25 (1008.75, 16548.75)
AN (sec) 395.10 + 20.35 416.86 (42.86, 573.75) 468.87 + 6.70c 470.00 (383.33, 542.67)
TN/A (sec h21 awake) 117.17 + 13.01 115.41 (2.48, 267.40) 530.83 + 45.25c 511.55 (64.21, 1054.34)
Means differ statistically significantly from the respective control group.

a
p , 0.02;
b
p , 0.005;
c
p , 0.001;
ns
Not significant.
1. computation of the dichotomy index (I , O);

2. computation of r24 from autocorrelation analysis; and
3. analysis and comparison of activity data in the form of 15 min
averages.
The average dichotomy index was statistically significantly lower in the

group of cancer in-patients than the respective control subjects. This
clearly suggests that the studied cancer patients did experience heightened
sleep difficulties. Similar observations were previously reported (Mormont
& Waterhouse, 2002; Mormont et al., 2000). The latter showed that the
dichotomy index (I , O) is usually best correlated to quality of life
(QoL). Therefore, the studied cancer patients are presumed to have had
a poor QoL. Furthermore, the average autocorrelation coefficient (r24)
was lower among the cancer patients, although it was not statistically sig-
nificantly different from that of the group of control subjects. Taken
together, the findings suggest that circadian rhythm parameters, especially
the amplitude and acrophase, of the rest-activity are greatly affected by the
disease conditions. In addition, the average level of activity, when com-
puted at intervals of 15 min, was drastically lower among the cancer
patients as compared with the control subjects. Waveforms were also com-
pared based on harmonic means of the mesors, amplitudes, and acro-
phases obtained independently by cosinor analysis at fixed windows with
period equals to 24 h and 12 h for both cancer in-patients and control sub-
jects. From this comparison, it was revealed that the bimodality in the rest-
activity rhythm was greatly dampened in the group of cancer in-patients as
compared with the control subjects.
The results of the present study, therefore, document that the disrup-
tion of circadian rest-activity rhythm of cancer in-patients is characterized
by dampening of amplitude, lowering of mean activity level, and phase
advancement. These alterations of circadian rhythm characteristics could
be attributed to disease. It is important to mention here that all cancer
patients under investigation in the present study were in-patients,
although they were ambulatory within and outside the ward in the pre-
mises of the hospital. The characteristics of the rest-activity circadian
rhythm in out-patients may differ from that of in-patients. However, this
aspect has not been examined in the present study. The present study
suffers from the deficiencies in that it did not have in-hospital control sub-
jects, although it is highly desirable. It was not feasible to incorporate such
control subjects because admission to the hospital is restricted to severely ill
patients. Further appropriate in-house control groups were also not avail-
able. Therefore, the interpretation and application of the findings of the
present study have to be done with caution, especially because in-house
patients spent much time sitting and waiting to be examined by doctors.
Thus, their level of activity was limited by hospital routine, which may
noticeably influence the characteristics of circadian rhythm.
Age-related decrements in sleep and daytime alertness levels have
been documented in human subjects. This phenomenon has been attribu-
ted to the weaker circadian regulation of sleep and wakefulness (Cajochen
et al., 2006). Paradoxically, persistence of lifestyle regularity has been
reported in adults and seniors (Monk et al., 2006). It is difficult to
explain how both weak circadian organization and lifestyle regularity
coexist among senior subjects. The dampening of the circadian amplitude
in cancer patients has not been examined categorically as function of age
and gender in previous investigations (Chevalier et al., 2003; Kobayashi
et al., 2002; Lévi, 2006; Mormont & Lévi, 2003). However, it has been
reported that the distribution of the 24 h rest-activity cycle parameters is
independent of gender, age, primary tumor, number of metastatic sites,

and prior treatment (Mormont & Waterhouse, 2002). Further, a signifi-
cant correlation between actigraphy measures and age was not apparent
in breast cancer patients (Roscoe et al., 2002). However, it has to be empha-
sized that gender is an important factor in studies that involve sleep and
circadian rhythms in young human subjects (Goel et al., 2005). These
authors have reported better sleep quality in women than men across
several consecutive nights.
It seems that the rest-activity circadian rhythm is not easily abolished or
masked by cancer diseases, irrespective of type, stage, and performance
status of the cancer. Nonetheless, results of earlier studies reveal the mag-
nitude of alteration, but not the absence of significant circadian rhythms, in
the characteristics of rest-activity or hormonal rhythms could vary as func-
tion of the severity of the disease (i.e., performance status and stage; see
Bartsch et al., 1994; Mormont & Lévi, 1997; Mormont et al., 2000;
Touitou et al., 1995). Significant alterations in circadian rhythms have
been reported in patients with large tumor burden, liver metastasis,
poor performance status, and advanced stage (Mormont & Lévi, 1997;
Mormont et al., 2000).
The results of the present study reconfirm those of other reported findings
(Levin et al., 2005; Mormont et al., 2000; Pati et al., 2006) in that the 24 h
average and amplitude of the rest-activity circadian rhythm decline drasti-
cally and the acrophase advances significantly in cancer patients compared
with the age- and gender-matched apparently healthy subjects. In the
present study, the acrophase occurred earlier in the cancer in-patients;
similar phase advancement has been reported before (Chevalier et al.,
2003). Rhythm alterations may depend upon tumor type, growth rate,
and extent of tumor differentiation (Lévi, 2006). It has been argued that
because patients with abnormal rest-activity cycle have elevated levels of
TGFa, TNFa, and IL-6, the rhythm alteration could be ascribed to the
tumor itself through the release of cytokines and growth factors (Lévi,
2006). These factors have been known to alter the circadian organization
of humans (Rich et al., 2005). In the present study, an inter-individual vari-
ation in the occurrence of the circadian acrophase was noticed in the group
of cancer patients. This could be the reason why the outcome of therapy of
individual cancer patients varies dramatically. This result strongly advo-
cates the implementation of patient-specific chronotherapy. In a recent
paper, Lévi & Schibler (2007) envisaged a custom-tailored medicine in
the future. This is based on the concept of cellular heterogeneity of
cancers that gives rise to individual variability in the expression of
rhythm characteristics.
Sleep-wake disturbances in patients with head and neck (Pati et al.,
2006) and colorectal (Chevalier et al., 2003) cancer have been reported.
Although sleep efficiency, sleep latency, and actual wake time in cancer
patients did not differ from that of the control group of healthy subjects,
other sleep parameters (i.e., time in bed and assumed and actual sleep
times) did differ in a statistically significant manner. In contrast to
control subjects, cancer patients spent a longer duration in bed and exhib-
ited longer assumed and actual sleep. Although Berger et al. (2005) and
Levin et al. (2005) reported that cancer patients do experience sleep/
wake disturbances, information about individual sleep parameters in
cancer patients is limited. Recently, Fernandes et al. (2006) documented
a significant difference in several sleep parameters, namely % sleep,
sleep efficiency, and wake after sleep onset, between cancer patients and
healthy volunteers. Other reports also documented that cancer patients
tend to have fragmented sleep and poorer sleep efficiency, exhibit more
restlessness at night, and take longer time to fall asleep (Ancoli-Israel
et al., 2006; Berger, 1998; Miaskowski & Lee, 1999; Mormont et al.,
1996). In addition, in the present study, the cancer patients exhibited
more episodes of wake and sleep bouts during the habitual sleep period.
It seems that in cancer patients, longer time in bed and longer assumed
sleep are a usual phenomenon. Both the frequency and duration of naps
during the awake-span were higher among the cancer patients. This
finding supports the results of previous studies in that daytime naps
were reported in patients with bone metastasis and breast cancer
(Ancoli-Israel et al., 2006; Miaskowski & Lee, 1999). Together, these
alterations could lead to circadian rhythm alterations characterized by
decreased amplitude and low 24 h average activity.
In conclusion, the results of the current study found that cancer
patients and controls exhibit 24 h rest-activity rhythmicity, but the
cancer in-patients exhibited lower amplitude, lower mean activity level,
and earlier acrophase compared to controls. These alterations were inde-
pendent of gender and site of cancer. These results might help in design-
ing patient-specific chronotherapeutic protocols.
ACKNOWLEDGMENTS
The research was supported by the University Grants Commission,
New Delhi, under its DRS-Special Assistance Program, and Department
of Science and Technology, New Delhi, under the SERC FAST Track
Scheme and DST-FIST program. The authors gratefully acknowledge
all cancer patients and control subjects for their voluntary participation
in the study. We thank Professor Michael Smolensky and two unknown
referees for reading an earlier version of this paper and for offering
numerous constructive suggestions.
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ALTERATIONS OF THE CHARACTERISTICS OF THE CIRCADIAN

Atanu Kumar Pati,1 Arti Parganiha,1,2 Anjana Kar,1 Rakesh Soni,1

alterations of the circadian rhythm characteristics could be attributed to disease,

Keywords Rest-activity pattern, Circadian rhythm, Head and neck cancer,

The clinical relevance of these findings has been amply validated in

PATIENTS AND METHODS

and clinical characteristics of the in-patients and apparently healthy sub-

Assessment of the Characteristics of Circadian Rest-Activity

Number of patients (M/F) 31 (19/12)

signals), a filter that excludes external vibrations by selectively registering

Study of Sleep Parameters

In addition, either the patients or their attendant recorded the bedtime,

dichotomy index, I , O, differences in activity distribution between the

FIGURE 1 Illustrative examples of double-plotted rest-activity profile (actogram) in cancer in-patients

Cancer patients Control subjects Cancer vs.

period of 24 h, most of them exhibited a secondary peak at 12 h. This

Circadian 24 h Average (Mesor)

count, obtained at the fixed window with t ¼ 24 h, was expressed as

Circadian Peak (Acrophase)

Dichotomy Index (I < O)

Autocorrelation Coefficient (r24)

Peak (Acrophase) Map

Sleep and Nap Parameters

Means differ statistically significantly from the respective control group.

1. computation of the dichotomy index (I , O);

The average dichotomy index was statistically significantly lower in the

independent of gender, age, primary tumor, number of metastatic sites,

ican Cancer Society. 9:155–169.

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