[Chronotherapy in oncology. Medical strategy. Care of a patient in chronotherapy].
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Antineoplastic Agents↗
Biomedical subjects
F Lévi
Publications and source records attributed to F Lévi.
Serum thymidine kinase levels are elevated and exhibit diurnal variations in patients with advanced ovarian cancer.
Deoxythymidine kinase (TK) is an enzyme involved in DNA synthesis whose serum activity reflects the proliferative activity of tumors and correlates with prognosis in various malignancies. In ovarian cancer, the value of s-TK has not been studied so far. Therefore the serum levels of TK were investigated in patients with advanced ovarian cancer. Because considerable diurnal fluctuations of s-TK levels were reported previously, repeated determinations were performed over a 48-h time span. Fourteen patients (mean age +/- S.D., 56.1 +/- 8.0 years) with advanced ovarian cancer and five healthy volunteers (30.2 +/- 3.5 years) were studied. Serial determinations of s-TK and serum CA 125 (s-CA 125) levels were performed over a 48-h time period. S-TK and s-CA 125 were elevated (> 4.7 U/l and > 35 U/ml) in 10 patients at least once over the 48-h period, respectively. Linear regression analysis showed a strong correlation between s-TK and s-CA 125. However, three patients with consistently normal s-CA 125 values (< or = 35 U/ml) had elevated s-TK levels, indicating that these two parameters may be independent in some patients. Both s-TK and s-CA 125 levels showed considerable diurnal changes over the 24-h period in individual patients, in marked contrast to normal subjects. Individual peak-trough differences ranged from 0.1-8.5 U/l or 5-268% for s-TK, and from 4-75 U/ml or 15-100% for s-CA 125. Peak-trough differences of s-TK > or = 100% were found in five patients. The circadian fluctuations of s-TK and CA 125 did not show a regular circadian pattern nor any temporal covariation. This study demonstrates for the first time that s-TK levels may be elevated in ovarian cancer. In some patients, s-TK levels may exhibit considerable, irregular diurnal fluctuations. Repeated determinations should therefore be performed in situations where this marker is relevant for patient monitoring.
Adult↗
Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy.
BACKGROUND: The efficacy of chemotherapy may be affected by circadian rhythms. Therefore, we tested chronomodulated infusion (administered to coincide with relevant circadian rhythms) of oxaliplatin, fluorouracil, and folinic acid compared with a constant-rate infusion method. The combination of three drugs was delivered for 5-day courses with 16-day intervals. METHODS: We expected chronotherapy to increase objective response rate by 20% compared with constant-rate infusion. We tested this effect in a randomised multicentre trial involving patients with previously untreated metastases from colorectal cancer who were enrolled at nine institutions in three countries. 93 patients were assigned chronotherapy and 93 were assigned constant-rate infusion via multichannel programmable ambulatory pumps. The trial was interrupted when a significant difference in main outcome was reached. All data were analysed by intention to treat. FINDINGS: On enrollment, we found significant imbalances in two characteristics-abdominal gland or bone metastases (constant-rate infusion two patients, chronotherapy ten patients) and relapse from surgically treated metastases (constant-rate infusion seven patients, chronotherapy 22 patients). An objective response was obtained in 47 (51%) of the chronotherapy group, and in 27 (29%) of the constant-rate group (difference 21.5% [95% CI 13.7-31.2], p = 0.003). Chronotherapy reduced five-fold the rate of severe mucosal toxicity (14% vs 76%, p < 0.0001) and halved that of functional impairment from peripheral sensitive neuropathy (16% vs 31%, difference 15.0% [9.5-25.7], p < 0.01). Median time to treatment failure was 6.4 months on chronotherapy and 4.9 months on constant-rate infusion (p = 0.006), and 24% of the patients from the constant-rate infusion group received chronotherapy after failure. With a minimum follow-up of 3 years, median survival times and 3-year survival were similar in both groups (15.9 vs 16.9 months and 22% vs 21%, respectively). INTERPRETATION: Chronotherapy was significantly less toxic and more effective than constant-rate infusion. The results support the concept of temporal selectivity of cancer chemotherapy.
Adult↗
Circadian-system alterations during cancer processes: a review.
Murine and human data have indicated that tumors and tumor-bearing hosts may exhibit nearly normal or markedly altered circadian rhythms. Amplitude damping, phase shifts, and/or period (tau) change, including appearance of ultradian rhythms (with tau < 20 hr) usually become more prominent at late stages of cancer development. The extent of rhythm alterations also varies according to tumor type, growth rate and level of differentiation. While "group chronotherapy," i.e., administration of the same chronomodulated schedule to cancer patients, has increased chemotherapy efficacy and/or tolerability, cancer patients' individual circadian rhythms now need to be explored on a large scale, in order to estimate the incidence of cancer-associated circadian-system alterations and to understand the underlying mechanisms. Correlations between such alterations and patient outcome must be established in order to specify the need for individualized chronomodulated delivery schedules and/or specific rhythm-oriented therapy, especially in patients with circadian-system disturbances.
Animals↗
A phase I trial of 5-day chronomodulated infusion of 5-fluorouracil and 1-folinic acid in patients with metastatic colorectal cancer.
The aim of this phase I study was to establish the maximum tolerated dose (MTD) of 5-fluorouracil (5-FU), administered as a 5-day chronomodulated infusion in combination with 1-folinic acid (FA) to ambulatory metastatic colorectal cancer patients. Consecutive cohorts of 6 patients were given 5-FU and FA infusions from 10.00 p.m. to 10.00 a.m. with peak delivery at 4.00 a.m. by means of a multichannel programmable pump. The FA dose was always the same (150 mg/m2/d). For the first cohort, the 5-FU dose level was 600 mg/m2/d at the first course, escalated by 100 mg/m2 for each subsequent cohort. Intrapatient dose was also escalated by 100 mg/m2 if toxicity was less than grade 2. The courses were repeated every 3 weeks. Thirty-four patients (17 previously treated) received a total of 154 courses. Dose-limiting toxicity consisted of stomatitis and diarrhoea. No significant haematological, cutaneous or cardiac toxicity was encountered. The MTD of 5-FU was reached at the fourth level (first course at 900 mg/m2/d equal to 4500 mg/m2/course) with 5-FU increased to 1100 mg/m2/d (5500 mg/m2/course) in 4 patients. The received 5-FU dose intensity (DI) over the first 3 courses at this level was 1318 mg/m2/week. Thirty-three patients were assessed for response. An objective response was achieved in 1 out of the 13 previously-treated and in 8 out of the 20 previously-untreated patients. The chronomodulated infusion of 5-FU at a dose of 900 mg/m2/d, together with FA at 150 mg/m2/d for 5 days, was safely delivered to out-patients with metastatic colorectal cancer. The low toxic profile and activity of this regimen in previously untreated patients deserves further exploration for the treatment of 5-FU-sensitive tumours.
Adenocarcinoma↗
Persistent T lymphocyte rhythms despite suppressed circadian clock outputs in rats.
Circadian rhythms in circulating leukocyte and lymphocyte counts persisted with halved amplitudes in constant light (LL) of 300 lx intensity for 8 wk, whereas circadian rhythms in body temperature, locomotor activity, and plasma catecholamines were completely suppressed. Subsequent exposure to constant darkness (DD) normalized all circadian rhythms within 2 wk. Rhythms in circulating T lymphocyte subsets were studied in LL or DD using double labeling with monoclonal antibodies and flow cytometry. Circadian rhythms were suppressed for leukocytes and lymphocytes but were maintained for both T helper cells (Th) and T cytotoxic cells (Ts) lymphocytes after 11 wk in LL. A group 24-h rhythm was only validated for total lymphocytes after 16 wk in LL. However, individual total, Th, and Ts lymphocytes maintained their usual respective phase relationships in each rat. The alteration of immune cell circulatory rhythms likely stemmed from a progressive loss of circadian synchronization among rats kept in LL. Conversely, after 11 or 16 wk in DD, leukocytes and lymphocyte subsets circadian rhythms were maintained. Thus catecholamines do not drive circulatory T cell rhythms. The loss of coupling between T lymphocyte rhythms and three major outputs of the circadian system further supports the hypothesis of an independent immunologic oscillator.
Animals↗
Melatonin high-affinity binding to alpha-1-acid glycoprotein in human serum.
The binding of 3H-melatonin to human serum proteins was investigated by equilibrium dialysis at 37 degrees C and pH 7.4. The binding to serum was moderate (53%) for physiological melatonin concentrations below 1 nmol/L. alpha 1-Acid glycoprotein and albumin bound melatonin with high 27 +/- 3 and low 1.5 +/- 0.1 (mmol/l)-1 affinity, respectively. Melatonin binding to other serum proteins, gamma-globulins and lipoproteins was not significant. The serum binding was characterized by a saturable and a nonsaturable component. The saturable component resulted from the high-affinity binding to alpha 1-acid glycoprotein and the nonsaturable component resulted from the low-affinity binding to albumin. The number of binding sites was 0.36/molecule of alpha 1-acid glycoprotein, when either pure alpha 1-acid glycoprotein or serum were studied, indicating that only a fraction of alpha 1-acid glycoprotein bound melatonin. The observed binding parameters did not enable simulation of the observed serum binding, and melatonin binding to an alpha 1-acid glycoprotein-albumin mixture was higher than that expected from the binding to each isolated protein. The high-affinity melatonin binding to alpha 1-acid glycoprotein might result from a potentiation of the binding interaction by albumin and the amount of melatonin bound in plasma might vary according to the alpha 1-acid glycoprotein concentration.
Blood Proteins↗
Pharmacokinetically guided melatonin scheduling in rats with circadian system suppression.
To obtain a pharmacologic effect of melatonin in rats kept under prolonged continuous light exposure, conditions known to produce functional suppression of the circadian system, mimicking of the physiologic 24-h pattern of melatonin secretion, a hormonal signal of darkness exposure may be needed. The delivery scheme for melatonin was established in rats in the present studies. First, the plasma pharmacokinetics of [3H]melatonin were determined in rats kept under continuous light and in rats synchronized by exposure to alternating 12 h light and 12 h darkness (LD 12:12) in the early light span. The pharmacokinetics of total radioactivity were similar in both groups. Further quantitation of melatonin by thin-layer chromatography revealed differences dependent on light conditions. The mean plasma clearance and steady-state distribution volume were approximately twice as low with continuous light as with LD 12:12. Plasma protein binding of melatonin was approximately 33%, irrespective of group or sampling time. These pharmacokinetic parameters were used to devise a 24-h periodic delivery schedule consisting of a 6-h constant infusion of exogenous melatonin, followed by an 18-h melatonin-free interval. In a second study, the melatonin 24-h pattern was estimated from the measurement of 2-h fractions of urinary 6-sulfatoxymelatonin excretion for 4 days. 6 unrestrained rats kept under continuous light received melatonin for 2 days from 22:00 to 04:00 h through an indwelling jugular catheter, connected to a reservoir from a programmable pump. Only the administration of low doses (0.01 mg/kg/day) resulted in both a circadian pattern for 6-sulfatoxymelatonin excretion and normal physiological values during the infusion-free intervals. The resynchronizing efficacy of this schedule should be tested in rats with functional suppression of the circadian system.
Animals↗
Multiple primary cancers and estimation of the incidence rates and trends.
The use of different registration rules from one registry to another, both generally and also for paired organs, leads to variations in the proportion of multiple primary cancers: in men, from 0.4 to 4.9% for the colon, 0.1 to 2.7% for the lung, and 4.1 to 8.6% for the mouth and pharynx. Subjective factors, often impossible to verify, contribute to these variations. The impact on the estimation of incidence rates and trends is not negligible for cancers of the mouth and the pharynx and for all the cancers taken together. The trend towards an increase of cancers of the mouth and pharynx in the Bas-Rhin disappeared when the incidence was expressed taking only the first cancer (incidence by individual) into consideration, and the differences in incidence between the Calvados and the Bas-Rhin registries for the same site also disappeared. In the absence of harmonisation of the rules and methods followed for registration, incidence by individual is the only approach which makes it possible to compare incidence rates and trends between registries.
Breast Neoplasms↗
Disruption of the circadian patterns of serum cortisol in breast and ovarian cancer patients: relationships with tumour marker antigens.
Few data are available on the circadian rhythmicity in cancer patients. Since monitoring the disease usually implies the follow-up of blood concentrations of a number of biological variables, it would be of value to examine the profile of the circadian variations of serum cortisol and tumour marker antigens. This we did in 33 cancer patients (13 breast cancer patients and 20 ovarian cancer patients). The profiles of serum cortisol were documented, since this hormone is considered as a strong marker of circadian rhythms. This study shows that 8 out of 13 breast cancer patients and 15 out of 20 ovarian cancer patients had deeply altered cortisol circadian patterns. The modifications were either high levels along the 24 h scale and/or erratic peaks and troughs and/or flattened profiles. Within 24 h, variations of tumour marker antigens as large as 70% were observed but no typical individual circadian patterns could be found. No relationship between cortisol subgroups and concentration of tumour marker antigens at 8 h could be observed (Kolmogorov-Smirnov's test). The question thus arises as to the origin of these alterations, and whether they are related to a cause or a consequence of the disease, and their possible incidence upon therapeutic designs.
Adult↗
Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy.
OBJECTIVE: The authors discuss the technique and evaluate the results of an aggressive surgical approach in patients with primarily unresectable colorectal liver metastases that were downstaged by chronomodulated chemotherapy. BACKGROUND: Resection is the best treatment of colorectal liver metastases, but it may be achieved in only 10% of patients. In the remaining 90%, survival is poor, even after partial response to chemotherapy. Little is known about the results of curative hepatectomy in patients whose metastases are downstaged by chemotherapy. PATIENTS AND METHODS: Fifty-three patients with colorectal liver metastases initially unresectable because of ill located (8), large (8), multinodular (24) lesions, or because of extrahepatic disease (13) were downstaged by a systemic chronomodulated chemotherapy associating 5-fluorouracil, folinic acid and Oxaliplatin to the point that operation could be performed. This consisted of a major hepatectomy in 37 patients and a minor resection in 16. Associated procedures (including 5 two-stage hepatectomies and 3 pulmonary resections) were performed in 25 patients. RESULTS: There was no operative mortality. Complications occurred in 14 patients. The cumulative 3- and 5-year survival rates were 54% and 40% (according to the type of lesions: ill-located, 75% and 48%; large, 62% and 62%; multinodular, 54% and 40%; extrahepatic, 43% and 14%). Hepatic recurrence (34 patients, 64%) was amenable to repeat surgery in 15 cases. CONCLUSIONS: Liver resection may be achieved in some previously unresectable patients with the help of an effective chemotherapy. The benefit in survival seems comparable to that obtained with primary liver resection (40% at 5 years). This therapeutic strategy involves a multimodal approach, including repeat hepatectomies and extrahepatic surgery.
Aged↗
Chronotherapy for gastrointestinal cancers.
Chronotherapy consists in the administration of medicines according to biological rhythms. Further insight into the mechanisms of the circadian system has led to adapting the delivery of cancer chemotherapy to rhythms in drug metabolism or cell proliferation. The pharmacology of anticancer agents has long been known to vary largely and predictably according to dosing time in mice or rats. Portable programmable multi-channel pumps allowed demonstration of the clinical relevance of the chronotherapy principle in a sufficiently large patient population. This demonstration was achieved using a 5-day infusion of 5-fluorouracil, leucovorin, and oxaliplatin in patients with colorectal cancer metastases. A further innovation was that oxaliplatin, a new drug whose activity in this disease was first shown using chronomodulated infusion, was incorporated early in this novel three-drug regimen, in view of the good tolerability of this administration schedule. The fully ambulatory nature of treatment courses was an additional constraint put on chronotherapy. More than 1000 patients with metastatic gastrointestinal malignancies have now received chronotherapy protocols in several countries from North America or Europe. Results have clearly indicated that this approach improved chemotherapy tolerance and allowed safe increases in drug doses. A clinical phase III trial compared a flat versus the chronomodulated three-drug regimen, and demonstrated large, simultaneous improvements in both tolerability and response rates in patients with metastatic colorectal cancer receiving chronotherapy. This approach may also be beneficial to patients with other gastrointestinal malignancies, and it was amenable to combination with surgery and radiotherapy. It also appeared suitable for devising potentially more active dose-intensive yet safe regimens. Incorporation of chronopharmacology into the development stages of new drugs may improve their safe use to the greatest benefit of both cancer patients and new drug development, as was done for oxaliplatin.
Antineoplastic Agents↗
Modulation of cisplatin chronotoxicity related to reduced glutathione in mice.
Intracellular reduced glutathione (GSH) concentrations were measured according to the tissue sampling-time along the 24 h scale in male B6D2F1 mice. A significant circadian rhythm in GSH content was statistically validated in liver, jejunum, colon and bone-marrow (P < or = 0.02) but not in kidney. Tissue GSH concentration increased in the dark-activity span and decreased in the light-rest span of mice. The minimum and maximum of tissue GSH content corresponded respectively to the maximum and minimum of cisplatin (CDDP) toxicity. The role of GSH rhythms with regard to CDDP toxicity was investigated, using a specific inhibitor of GSH biosynthesis, buthionine sulfoximine (BSO). Its effects were assessed on both tissue GSH levels and CDDP toxicity at three circadian times. BSO resulted in a 10-fold decrease of the 24 h-mean GSH in kidney. However a moderate GSH decrease characterized liver (-23%) and jejunum (-30%). BSO pretreatment largely enhanced CDDP toxicity which varied according to a circadian rhythm. Although BSO partly and/or totally abolished the tissue GSH rhythms, it did not modify those in CDDP toxicity. We conclude that GSH have an important influence on CDDP toxicity but not in the circadian mechanism of such platinum chronotoxicity.
Animals↗
Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.
PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.
Adolescent↗
[Analyses of rhythms of the body temperature in free running in rats].
We have previously observed a light-induced suppression of circadian rhythms of body temperature and locomotor activity in 50/55 male Sprague Dawley rats (Am. J. Physiol., 1995). This study presents a description of 4 records of body temperature obtained by telemetry and compares three methods of period analysis (Fourier analysis, autocorrelation and cosinor). In case of persistant circadian rhythms, Fourier analysis and cosinor method agree and allow description of rhythm parameters. However, in case of an alteration of the circadian system in continuous light, these 2 methods can disagree on the dominant period. Autocorrelation analysis permits to conclude on the absence of circadian and ultradian rhythmicity. These results demonstrate the necessity to associate several methods for period analysis and plaids for the development of a strategy for data processing of longitudinal time series.
Animals↗
[Study of circadian rhythms of activity by actometry: preliminary results in 30 patients with metastatic colorectal cancer].
Activity circadian rhythms were measured non-invasively in 30 patients with metastatic colorectal cancer by wrist actigraphy, and compared with control data. Patients and control subjects were requested to wear the actigraph at home for 2 to 5 days. Control time-series exhibit high activity levels (150 to 350 counts/min) during daytime, followed by low activity levels (0 to 50 counts/min) during the night. In patients, the contrast between daytime activity and nocturnal sleep is noticeably less marked, and a wide inter-patient variability can be observed. This alteration of the rest-activity rhythm in the cancer group was statistically validated by autocorrelation test. Results from the cosinor and he maximal entropy spectral analysis must be interpreted more cautiously, since the prerequisites for these tests may not be fulfilled by actometric time-series. These results indicate that cancer patients may have altered rest-activity circadian rhythms. The significance and prognostic value of such alterations deserve further testing in a larger population. Actigraphy may provide a simple and innovative tool to study the circadian system in cancer patients.
Adenocarcinoma↗
[Rhythmic component of twelve hours].
From observations made on the rhythms in different systems: changes in plasmatic concentrations of 5-fluorouracil administered at a constant rate, proliferative activity of human tissues (bone marrow and oral mucosa), actometry, variations of glutathione levels in the liver and kidney from ice, we show the existence of a 12 hours rhythmic component and we discuss the putative importance of this component.
Adult↗
[Chronopharmacology and chronotherapy of cancers].
Tolerability of approximately 30 anticancer drugs vary by 50% or more according to circadian rhythms in mice or rats. Despite pharmacokinetics parameters of cytostatic drugs vary according to dosing time in rodents, cellular rhythms appear as the main mechanisms of their chronopharmacology: circadian changes in enzymatic activities involved into fluoropyrimidine (5-fluorouracil-5-FU, or floxuridine-FUdR) catabolism (dehydropyrimidine dehydrogenase) or anabolism (thymidine kinase), rhythms in reduced glutathione, involved into cellular protection against cytotoxic effects of alkylating drugs, platinum complexes and anthracyclines, rhythms in cellular proliferation of rapidly renewing tissues, such as bone marrow or intestinal tract. Furthermore, chemotherapy injection at the least toxic time allows to increase its antitumor efficacy against several transplanted rodent tumor models. Extrapolation of these results for improving therapeutic index of chemotherapy in cancer patients was based upon the hypothesis that rhythms in metabolism or proliferation of healthy tissues were tightly coupled to the circadian sleep-wakefulness cycle, both in rodents and in man. Programmable-in-time pumps allowed to test the clinical relevance of chronotherapy principle in patients with cancer metastases. Phase I clinical trials with 5-FU, FUdR, oxaliplatin-L-OHP, interferon-alpha and doxorubicin suggested that circadian-based chronomodulation of chemotherapy delivery rate both improved drug tolerability and allowed to increase its safe dose. Antitumor activity of such chronomodulated regimens, usually involving several drugs, appeared as superior to that achieved by standard protocols in Phase II clinical trials, especially in patients with renal cell cancer receiving FUdR and in patients with colorectal cancer treated with 5-FU, folinic acid (FA) and L-OHP (so called chrono-FFL regimen). A randomized european multicenter trial validated the clinical relevance of the chronotherapy principle in 278 patients with metastatic colorectal cancer: chrono-FFL was compared to flat FFL infusion and resulted in 2 to 10 times fewer severe toxic effects and a near-doubling of its antitumor efficacy, objective response rate being 51% with chrono-FFL and 30% with flat FFL (p < 0.001). These results have warranted to test further the relevance of chronotherapy in patients with breast, lung or pancreatic cancer metastases and to develop basic research on the role of biological rhythms upon cancer processes.
Animals↗