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Clinical Trials |
Laboratoire "Rythmes Biologiques et Chronothérapeutique," Université Paris XI and I.C.I.G., Hopital Paul Brousse, 94800 Villejuif, France [M-C. M., P. B., S. G., A. J., J-L. M., F. L.]; School of Human Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom [J. W.]; Département de Biochimie Médicale, Hopital de la Pitié-Salpêtrière, 75013 Paris, France [A. B., Y. T.]; and INSERM U 472, 94800 Villejuif, France [J. L.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In humans, the rest/activity rhythm is considered, and used as, a marker of the endogenous circadian clock function in isolation studies (6, 7, 8) , in phase-shift studies (9, 10, 11) , and in psychiatry (12, 13, 14) The rest/activity rhythm is a better marker of the human circadian system than cortisol or leukocytes, which interfere with and may be affected by peripheral physiological changes (reviewed in Ref. 15 ). However, the clinical relevance of the rest/activity rhythm has not yet been addressed in cancer patients.
The administration of anticancer agents at specific stages of the rest/activity cycle improves their therapeutic index in laboratory rodents (16) . Time-qualified chemotherapy (chronotherapy) was first successfully used for ovarian cancer (17 , 18) . An appropriate adjustment of chemotherapy delivery to circadian rhythms became feasible with the advent of multichannel programmable pumps and led to the clinical validation of the chronotherapy principle in Phase I, II, and III clinical trials involving >1500 patients with metastatic colorectal cancer (19, 20, 21, 22) . More specifically, chronotherapy with 5-fluorouracil, leucovorin, and oxaliplatin reduced by 5-fold the incidence of severe mucositis, halved the incidence of functional impairment from peripheral sensory neuropathy, and nearly doubled the objective response rate compared with constant infusion (21) . Nevertheless, interpatient variability was observed, indicating that factors other than the timing of treatment influenced outcome.
Cancer processes can alter circadian function in both experimental tumor models and patients (23) . Thus, variability in the outcome of patients receiving chronotherapy may reflect differences in individual circadian rhythms. If so, these rhythms may constitute novel prognostic factors, possibly independent from the clinical factors, which mostly reflect tumor spread (24, 25, 26) . The status of the circadian system as an estimate of cancer patients’ prognosis was first tested in two pilot studies. The first study investigated individual rhythms in relation to clinical predictors for survival in 20 patients with advanced ovarian cancer. Significant correlations were found between well-documented prognostic factors, such as the WHO PS3 or tumor size, and the circadian amplitude in serum cortisol and leukocyte or neutrophil counts (27) . The second study indicated that circadian rhythm alterations were associated with both poor PS and liver metastases in 13 patients with advanced breast cancer (28) .
This prospective study was initiated to evaluate the prognostic value of circadian rhythms in patients with metastatic colorectal cancer. The primary hypothesis was that altered rest/activity rhythms would predict for shorter survival. Maximum tumor response and QoL were secondary end points of patient outcome. Additional exploratory analyses were performed to determine whether clinical prognostic factors, other marker circadian rhythms, or QoL factors such as fatigue, sleep disturbances, and pain significantly influenced the relationship between the rest/activity rhythm and survival.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. All patients were followed for survival until February 1, 1998, when
126 deaths were recorded. Patients in poor general condition,
i.e., with PS, according to WHO, above 2, were not included
in the study, as is usual in oncology clinical trials. The initial
evaluation included a clinical examination, with PS assessment,
thoracic and abdominopelvic computed tomography scan and liver
echography. Serum CEA and CA19.9 were determined. Chronomodulated
chemotherapy consisted of the association of 5-fluorouracil (3200–3500
mg/m2/course; peak delivery at 4:00 a.m.)
and leucovorin (1200–1500 mg/m2/course; peak at 4:00 h); oxaliplatin was added to this two-drug regimen in 87% of
the patients (100–125 mg/m2/course; daily
maximum at 4 p.m.). Chronotherapy was delivered in fully
ambulatory conditions to all patients, using a multichannel
time-programmable pump (9, 10, 11, 12)
. Circadian rhythms in serum
cortisol and in leukocyte and neutrophil counts as well as the
rest/activity cycle were studied before the first cycle of
chronotherapy. Maximum tumor response to therapy was assessed every 2
months for the first 6 months by the investigators. Computed tomography
scans of the thorax, abdomen, and pelvis were generally complemented
with abdominopelvic ultrasonography and underwent extramural review.
Complete response was defined as a disappearance of all signs of
disease for 4 weeks, and partial response was defined as a reduction of
at least 50% in the area of all measurable lesions (20
, 21) . The Ethical Committee of Kremlin-Bicêtre (France)
approved the study, and each patient signed a written informed consent.
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The circadian rhythm in activity (main evaluation criteria) was
estimated by two parameters: autocorrelation coefficient at 24 h
(r24), and a dichotomy index (I<O) comparing amounts of
activity when in bed and out of bed. For the autocorrelation, if
Xi is the measurement at time
i, the correlation coefficient
rk, between
Xi and
Xi+k is computed for lags k,
with k = 1–4320 min (72 h); the coefficient at 24:00 h
(r24) can, in theory, range between -1 and 1. If there is a
circadian variation, the correlation coefficient will increase around
24-h lags, and a more pronounced circadian rhythm will result in a
higher coefficient at 24:00 h (Fig. 1
a; Ref. 30
). I<O is the percentage of the
activity counts measured when the patient is in bed that are inferior
to the median of the activity counts measured when the patient is out
of bed; thus I<O quantifies the level of activity during the rest
span, as defined in the patient’s diary. This index can theoretically
vary between 0 and 100%, and a high I<O reflects a marked
rest/activity rhythm (Fig. 1
b; Ref. 31
). Mean
activity was calculated for each patient and used as a secondary
criteria.
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QoL Assessment
QoL questionnaires were filled in by the patients before putting
on the actigraph. A study investigator was available for questions
about the study and how to fill in the forms.
QLQ-C30, from EORTC, is a 30-item questionnaire that incorporates five functional scales, eight symptom scales, and a global QoL scale (33 , 34) . The questions are formatted with either yes/no answers or with four-answer categories, except for the two questions on general QoL, which are to be answered on a scale numbered from 1 to 7. All calculations were performed after linearly transforming the scores to a 0–100 scale, according to EORTC guidelines (in EORTC QLQ-C30 scoring manual). Higher scores for the global QoL and functional scales represent better functioning, whereas higher scores on the symptom scales indicate a higher level of disturbance.
The HADS consists of seven items that evaluate anxiety and seven that aim at measuring depression; all questions are formatted with four-categories answers. Individual anxiety and depression scores range between 0 and 21 (35, 36, 37) .
Statistical Analysis
Descriptive Statistics.
Mean scores and SEs were calculated for all demographic, clinical
rest/activity or other rhythm-related as well as QoL parameters.
Normality of distributions was checked.
Primary Hypothesis.
Each of the main evaluation criteria (r24 and I<O) was
assigned to one of four categories according to quartiles, and the
survival of patients with very low (<25% quartile), low (>25% and
<50% quartile), high (>50% and <75% quartile), or very high
(>75% quartile) rhythm parameters was estimated with the Kaplan-Meier
method (38)
, with a comparison of the survival curves by
the log-rank test. A regression analysis was conducted on
survival time, measured from the date of activity rhythm recording,
with the Cox proportional hazard model (39)
.
Secondary and Exploratory Hypotheses.
Parametric or nonparametric (Kruskal-Wallis) ANOVAs were also used to
analyze mean rhythm or QoL parameters as a function of categorical
demographic and clinical characteristics. Possible associations between
rhythm parameters, QoL scores, and continuous clinical parameters were
tested with Spearman rank correlations. The influence of each
demographic, clinical, or rest/activity-related parameter on maximum
tumor response to treatment was assessed by single and multiple factors
linear regression. Finally, the multivariate Cox model was used to
determine which factors were jointly influential on survival
(39)
.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The three subjects on the left in Fig. 2
had a high mean activity
level. The first subject (Fig. 2
, top left-hand panel)
displayed a high activity level during the day, which decreased during
the night (rest) period: he had thus high rhythm parameters (I<O and
r24) The second subject (Fig. 2
, middle left-hand
panel) had a r24 above median (i.e.,
his activity pattern was highly reproducible) but a low I<O
(i.e., poor sleep), and the third subject (Fig. 2
,
bottom left-hand panel) had a low r24
(i.e., his activity pattern was not reproducible from 1 day
to the next) but a high I<O (he slept well when he was in bed). The
two subjects on the right in Fig. 2
had a low mean activity level: the
first subject (Fig. 2
, top right-hand panel) maintained a
marked circadian rhythm (high I<O and r24), whereas the
second subject (Fig. 2
, bottom right-hand panel) had
low circadian parameters with apparently altered periods of activity
and rest.
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Overall Treatment Efficacy.
Median survival was 13.2 months, with 31% of the patients alive at 2
years. Sixty-seven patients displayed an objective response (35%),
among which 3 were complete. The disease was stabilized in 72 patients
(37.5%) and progressed in 53 patients (27.5%).
Influence of Rest/Activity Rhythms on Survival.
Marked circadian rhythms in activity, i.e., high
r24 (P < 10-4) and
high I<O (P < 10-4), predicted
for longer survival in the univariate Cox analysis. For graphic
purposes, each individual rhythm parameter was assigned to one of four
categories according to 25% quartiles. After a 2-year follow-up,
survival was 34% (95% CI, 26–43%) for the patients with
r24 in the three upper quartiles compared with 10% (95%
CI, 1–20%) for those whose r24 was in the lowest quartile
(Fig. 3
a). Similarly, 2-year survival was nearly 5-fold
higher for patients with I<O in both upper quartiles (38%; 95% CI,
27–49%) compared with those with I<O in the lowest quartile (8%;
95% CI, 1–15%; Fig. 3
b).
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Correlations between Rest/Activity and QoL.
Global QoL and physical functioning scores, as measured by EORTC
QLQ-C30, were positively correlated to circadian rest/activity rhythm
but not to the mean activity level. Fatigue and appetite loss were
associated with decreased circadian rhythm parameters and with
diminished mean activity, whereas pain was correlated with only one of
the rest/activity rhythm parameters (I<O). Patients’ self-rated sleep
difficulties were not significantly correlated to either the
rest/activity rhythm or to mean activity. From the HADS questionnaire,
depression was associated with damped circadian rhythms but not to low
mean activity (Table 2)
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Increased anxiety (P = 0.004), depression (P = 0.03), and decreased physical functioning (P = 0.05) were associated to rectal tumors. QoL scores did not vary as a function of any other clinical characteristics.
Prognostic Factors of Tumor Response.
Objective response rates differed significantly as a function of PS
(P < 10-4) and previous
chemotherapy for metastases (P = 0.04) in the
univariate analysis. This analysis also showed that the probability for
achieving an objective response was significantly influenced by the
rest/activity parameters r24 (P = 0.02) and
I<O (P < 10-4) as well as the
circadian rhythm estimate for leukocyte count (P =
0.006). The cortisol rhythm estimate did not influence objective
response.
In the multiple regression model, only PS (P = 0.02), circadian rhythm in WBC count (P = 0.03), and I<O (P < 10-4) were jointly influential on maximum response to treatment.
Global Survival Analysis.
Univariate survival analysis was performed for all clinical,
rhythm-related, and QoL variables. PS, number of metastatic sites, and
previous treatment for metastatic disease were strongly related to
survival. Patients with <25% liver involvement had a longer survival
than those with more extensive liver involvement or those with
extrahepatic metastases; the latter patients usually had lung
metastases associated with either peritoneal or bone metastases. High
levels of CA19.9 or CEA were associated with shorter survival (Table 4)
. In addition to both rest/activity rhythm parameters (I<O and
r24), mean activity was significantly related to survival as
well as the scores for global QoL physical functioning, fatigue,
appetite loss, pain, and depression (Table 3)
. No significant prognostic value was established for cortisol or
leukocyte rhythm estimates with regard to survival.
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. Finally, the
best fitting clinical prognostic model included liver involvement
(>25% versus 
25%), number of metastatic sites, previous
treatment for metastases, and PS (2 versus 0) jointly with
the rest/activity circadian rhythm and mean activity (Table 4)
. Thus, the circadian rest/activity rhythm added significant prognostic
information to the well-established clinical factors related to the
tumor or to the patient’s general condition (40)
. This
was also the case for mean activity, but to a lesser extent, as
documented by the smaller relative risk associated to this parameter.
To further determine whether rest/activity parameters provided
additional prognostic information to that already contained in PS, Cox
analysis was also performed separately in the subsets of patients with
PS = 0 or with PS = 1. Survival was still significantly
influenced by I<O in the subgroup of patients with PS = 0 and in
patients with PS = 1 (Table 5)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The rest/activity rhythm was a strong predictor of both tumor response and survival in patients with metastatic colorectal cancer. Each of the rest/activity-related variables provided additional prognostic information on patients’ maximum response to treatment and survival potential to that of well-known clinical factors that reflect tumor burden and patient general condition. The patients with poor circadian rhythmicity, i.e., with I<O in the lowest quartile, had a 5-fold higher risk of dying within 2 years than the patients with a better circadian rhythmicity. Furthermore, the prognostic value of I<O remained statistically significant in the subgroups of patients with PS = 0 or PS = 1 in both univariate and multivariate analysis. This result demonstrated that low rest/activity rhythm parameters did not merely reflect poor PS and further confirmed that the rest/activity rhythm was an independent prognostic factor.
Mean circadian changes in WBC counts were associated with activity rhythms, but the correlation was weak; this might account for the prognostic value of the circadian rhythm in WBC for response but not for survival. The estimate of the circadian rhythm in cortisol, another output variable of the circadian system, was not correlated to patients’ outcomes. This suggests that there is an uncoupling between different outputs of the circadian clock in some cancer patients. As documented by the association of cortisol mean concentration with poor-prognosis clinical characteristics, the secretion of cortisol may be directly influenced by tumor burden and spread, whereas the activity rhythm may reflect the global effect of the disease on the circadian clock function.
This study also documented the existence of a link between the
rest/activity rhythm and the welfare of cancer patients. Marked
rest/activity rhythms are associated with high functional scores and
low symptom scores. This is not surprising because several variables
evaluated in QoL questionnaires, such as locomotor activity, sleep, and
psychomotor performance, are organized along the 24-h time scale. I<O
appears to be the parameter that was best correlated to QoL. This
circadian index aims at quantifying sleep difficulties by comparing
activity values when in bed to the median value of activity when out of
bed for each 24-h period. This parameter differs from the usual end
points of sleep studies, such as timing of sleep onset, sleep latency,
duration, and timing of rapid eye movement (REM) sleep; these latter
items focus on a description of sleep timing, duration, and structure
and do not lead to a global scoring of the sleep phase. In the present
study, I<O correlates with the global estimate of QoL, physical
functioning, fatigue, appetite loss, and pain scores (Table 2)
but not
with patients’ subjective evaluation of sleep disturbances
(r = -0.14; P = 0.07). The statistical
analyses of this study indicate that the rest/activity rhythm does not
simply reflect confounding factors such as fatigue or pain: the
rest/activity parameters significantly improve the multivariate Cox
model for survival, whereas the QoL parameters, even if related to
survival, do not increase the significance of the model.
Diagnostic and therapeutic management as well as social or environmental factors exert a major impact on the QoL and outcomes of cancer patients (41, 42, 43, 44) . Moreover, this study suggests that the individual’s circadian system function is associated to some dimensions of a cancer patient’s psychological distress and QoL. Likewise, circadian system disturbances were reported in patients with neurological and/or psychological diseases (12, 13, 14, 15) . Although the issue of causal relationship may not be addressed in this study, these results open novel perspectives toward understanding the impact of cancer-induced circadian system alterations on the host physical and psychological balance.
There were previous indications that circadian rhythms can be altered in severe illness, the degree of abnormality being related to severity, as in cancer patients (27 , 28) and in patients in intensive care (44) . However, this study is the first to establish that an output rhythm of the circadian clock significantly predicts for survival in a prospective clinical trial. Furthermore, this investigation indicates that individual patients’ circadian function may provide a pertinent explanation for interindividual differences in the outcome of patients with colorectal cancer metastases. The scope of application of this concept now needs to be assessed with regard to chemotherapy schedule. The results call for further investigation of the relationship between cancer processes and circadian rhythm alteration, for devising specific therapies to restore the circadian rest/activity rhythm, and for testing the effect of such treatment in combination with chemotherapy on cancer survival.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by CNAMTS INSERM Grant 3
AM 055 and Réseau de Recherche Clinique INSERM 4R007A, Paris,
France; ARTBC Internationale, Villejuif, France; Compagnie de
Développement Aguettant, Lyon, France; and Grant Université
Paris XI-Debiopharm, Lausanne, Switzerland. 
2 To whom requests for reprints should be
addressed, at Hopital Paul Brousse, 14-16, Avenue Paul Vaillant
Couturier, 94800 Villejuif, France. Phone: 33 1 45 59 38 55; Fax: 33 1
45 59 36 02; E-mail: chronbio{at}club-internet.fr
3 The abbreviations used are: PS, performance
status, QoL, quality of life; CEA, carcinoembryonic antigen;
r24, autocorrelation coefficient at 24 h; I<O,
dichotomy index; EORTC, European Organization for Research and
Treatment of Cancer; HADS, Hospital Anxiety and Depression Scale; CI,
confidence interval.
Received 1/18/00; revised 4/18/00; accepted 5/ 4/00.
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REFERENCES |
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