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At least 19 recordsLinked to original sources
PubMed1997

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↗
PubMed2005

Alteration of the circadian rhythm in peak expiratory flow of nocturnal asthma following nighttime transdermal beta2-adrenoceptor agonist tulobuterol chronotherapy.

We investigated the efficacy of nighttime transdermal tulobuterol (beta2-adrenoceptor agonist) chronotherapy for nocturnal asthma by assessing changes both in the frequency of symptoms and features of the circadian rhythm in peak expiratory flow (PEF), a measure of airway caliber. Thirteen patients with nocturnal asthma were evaluated before and during tulobuterol patch chronotherapy, applied once daily in the evening for 6 consecutive days. Patients were asked to record their PEF every 4h between 03:00 and 23:00 h for one day. Circadian rhythms in PEF were examined by group-mean cosinor analysis. The group average PEF at 03:00 h, the time during the 24 h when PEF is generally the poorest, before the application of the chronotherapy, when asthma was unstable and nocturnal symptoms frequent, was 276 +/- 45 L/min. Application of the tulobuterol patch at nighttime significantly increased (p < 0.001) the 03:00 h group average PEF to 363 +/- 67 L/min. Significant circadian rhythms in PEF were observed during the span of study when nocturnal symptoms were frequent as well as with the use of the tulobuterol patch. Before the initiation of tulobuterol chronotherapy, the bathyphase (trough time of the circadian rhythm) in PEF narrowed to around 04:00h, and the group circadian amplitude was 28.8 L/min. In contrast, the group circadian amplitude significantly (p < 0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy. These changes indicate that tulobuterol chronotherapy significantly increased both the level and stability of airway function over the 24 h. The circadian rhythm in PEF varied with the severity and frequency of asthmatic symptoms with and without the nighttime application of the tulobuterol patch medication. We conclude that the parameters of the circadian rhythm of PEF proved useful both in determining the need for and effectiveness of tulobuterol chronotherapy for nocturnal asthma.

Administration, Cutaneous↗
PubMed2002

It's time for chronotherapy!

The EORTC Chronotherapy Group (CTG) stemmed from the International Organisation for Cancer Chronotherapy (IOCC) in 1996. The IOCC was first to initiate large scale multicentre international chronotherapy trials, for the purpose of investigating the relevance of chronomodulated or timed administration of cancer therapy based on biological rhythms. Programmable pumps for cytotoxic chronodelivery and actigraph devices to monitor circadian rhythm alterations linked to cancer were also developed. The unique expertise of the IOCC with regard to cancer chronotherapy furthered its development within the EORTC. The EORTC offers broad expertise in clinical cancer research and opportunities for scientific recognition, intergroup collaborations and translational research. Over the past 5 years, the EORTC CTG has grown from 16 to 48 centres in 12 different countries. It is currently conducting seven multicentre chronotherapy trials which test the relevance of adapting cancer treatment delivery to circadian rhythms. The group aims at developing multiple collaborations to establish a chronotherapy network involving institutions with expertise ranging from experimental chronobiology to new drug testing, disease-specific management and quality of life or survival issues.

Antineoplastic Agents↗
PubMed2003

It is time for chronotherapy!

The EORTC Chronotherapy Group (CTG) stemmed from the International Organisation for Cancer Chronotherapy(IOCC) in 1996. The IOCC was the first to initiate large scale multicentre international chronotherapy trials, for the purpose of investigating the relevance of chronomodulated or timed administration of cancer therapy based on biological rhythms. Programmable pumps for cytotoxic chronodelivery and actigraph devices to monitor circadian rhythm alterations linked to cancer were also developed. The unique expertise of the IOCC with regard to cancer chronotherapy furthered its development within the EORTC. EORTC offers broad expertise in clinical cancer research and opportunities for scientific recognition, inter-group collaborations and translational research. Over the past 5 years, EORTC CTG has grown from 16 to 48 centres in 12 different countries. It is currently conducting seven multicentre chronotherapy trials, which test the relevance of adapting cancer treatment delivery to circadian rhythms. The group aims at developing multiple collaborations to establish a chronotherapy network involving institutions with expertise ranging from experimental chronobiology to new drug testing, disease-specific management and quality of life or survival issues.

Antineoplastic Agents↗
PubMed1996

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↗
PubMed1999

Cancer chronotherapy.

The cytotoxicity of more than thirty anticancer drugs varies by more than 50% as a function of dosing time along the 24-h time-scale in laboratory animals. Mechanisms involve circadian changes in cellular metabolism and proliferation processes, as well as drug pharmacokinetics. Moreover, the administration of chemotherapy at the least toxic time usually achieves best antitumour efficacy in experimental tumour models. Here we review experiences in utilising these phenomena in the optimization of cancer chemotherapy in the clinic. Chronotherapy has been administered to 1500 patients with metastatic colorectal cancer using 5-fluorouracil and leucovorin with or without oxaliplatin. Sinusoidal chronomodulated delivery of 2- or 3-drug chemotherapy was performed in the patient's home or during usual activities, with a computer-programmed multi-reservoir pump. Courses lasted 4-5 days and were repeated every 14-21 days. Three-drug chronotherapy proved largely superior to flat infusion with respect to both tolerability and antitumour efficacy. The better tolerability of chronotherapy further allowed an increment of both 5-fluorouracil and oxaliplatin doses, which in turn further improved objective tumour response rate to 66%. This enabled surgical removal of previously inoperable metastases and the achievement of > 20% survival at three years. Second generation programmable-in-time pumps have simplified chronotherapy administration and decreased its costs. A broad use of fully ambulatory chronotherapy requires thorough definitions of drug stability, and compatibility with pump reservoirs and other medications.

Ambulatory Care↗
PubMed2003

Chronotherapy for cancer.

Cancer chronotherapy is attracting attention as a novel and logical therapy in which anti-cancer drugs are administered with optimal timing according to circadian rhythms of anti-cancer action and those of adverse effects on normal cells. Advances in chronobiology have identified the suprachiasmatic nucleus (SCN) as the center of biological rhythms and the area in which clock genes such as PER1, PER2, PER3, CLOCK, BMAL1, TIM, CRY1, CRY2, tau act to generate and coordinate biological rhythms. These findings have led to the development of chronotherapy. Clinically, patients with advanced gastrointestinal cancer have been treated by chronomodulated chemotherapy with good response. For colorectal cancer patients with unresectable liver metastases, chronotherapy with l-OHP + 5-FU + FA (folinic acid) has been reported to allow complete surgical resection of liver metastases, resulting in 39-50% 5-year survival. Many believe that chronotherapy will become accepted as a refined and advantageous therapeutic option for not only cancer but also for other diseases, due to its universally applicable principles.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Chronopharmacology and chronotherapy of cardiovascular medications: relevance to prevention and treatment of coronary heart disease.

Biological functions and processes, including cardiovascular ones, exhibit significant circadian (24-hour) and other period rhythms. Ambulatory blood pressure assessment reveals marked circadian rhythms in blood pressure both in normotensive persons and hypertensive patients, whereas Holter monitoring substantiates day-night patterns in electrocardiographic events of patients with ischemic heart disease. The concept of homeostasis, that is, constancy of the milieu interne, which has dominated the teaching, research, and practice of medicine during the 20th century,is now being challenged by emerging concepts from the field of chronobiology-the science of biological rhythms. Epidemiologic studies document the heightened morning-time risk of angina, myocardial infarction, and stroke. Circadian rhythms in coronary tone and reactivity, plasma volume, blood pressure, heart rate, myocardial oxygen demand, blood coagulation, and neuroendocrine function plus day-night patterns in the nature and strength of environmental triggers all contribute to this morning vulnerability. Homeostatically devised pharmacotherapies, that is, medications formulated to ensure a near-constant drug concentration, may not be optimal to adequately control diseases that vary in risk and severity during the 24 hours. Moreover, circadian rhythms in the physiology of the gastrointestinal tract, vital organs, and body tissues may give rise to administration-time differences in the pharmacokinetics and effects of therapies. Thus the same medication consumed in the same dose under identical conditions in the evening and morning may not exhibit comparable pharmacokinetics and dynamics. New technology makes possible chronotherapy, that is, increase of the efficiency and safety of medications by proportioning their concentrations during the 24 hours in synchrony with biological rhythm determinants of disease. The chronotherapy of peptic ulcer disease achieved by the evening dosing of H 2-receptor antagonists and of asthma by the evening dosing of special drug delivery forms of theophylline and morning methylprednisolone administration has proven to be beneficial. Controlled-onset extended-release verapamil constitutes the first chronotherapy of essential hypertension and ischemic heart disease; once-a-day bedtime dosing results in a high drug concentration in the morning and afternoon and a reduced one overnight. Studies demonstrate effective 24-hour control of blood pressure, including the attenuation of its rapid rise in the morning, without induction of nighttime hypotension. Moreover, this formulation effectively controls angina, especially in the morning when the risk of ischemia is greatest. Determination of the role of verapamil chronotherapy in the primary prevention of cardiovascular morbidity and mortality awaits the results of the CONVINCE trial now in progress.

Adrenergic beta-Antagonists↗
PubMed2001

Theophylline chronotherapy of nocturnal asthma using bathyphase of circadian rhythm in peak expiratory flow rate.

We studied the efficacy of theophylline chronotherapy for nocturnal asthma using the changes of the circadian rhythms in peak expiratory flow rate (PEF). Eight patients with nocturnal asthma were evaluated for the periods with nocturnal symptoms and with an evening dose of theophylline administered daily. Patients recorded their PEF every 4 hours on one of the days (from 7:00 to 23:00 h) in each period. Circadian rhythms in PEF were examined using the single and group-mean cosinor method. Significant circadian rhythms in PEF were observed in the period with nocturnal symptoms. When nocturnal symptoms were present, the bathyphase of PEF was present between midnight and morning. A significant circadian rhythm disappeared or PEF amplitude decreased during theophylline chronotherapy. The circadian rhythm in PEF was altered according to the severity of the asthma. In patients with symptoms present between midnight and early morning, an evening dose of theophylline chronotherapy can be prophylactically used for nocturnal asthma attacks. Consideration of the circadian rhythm and bathyphase of PEF is useful in selecting appropriate chronotherapy for nocturnal asthma.

Adult↗
PubMed2000

Circadian rhythm in peak expiratory flow: alteration with nocturnal asthma and theophylline chronotherapy.

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free peiiod. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms.

Adult↗
PubMed2002

Chronotherapy of colorectal cancer.

Chronotherapy consists of chemotherapy delivery according to circadian rhythms. These genetically based rhythms modulate cellular metabolism and cell proliferation in normal tissues. As a result, both the host tolerance and antitumor efficacy of 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), like 30 other anticancer drugs, vary largely according to the dosing time in laboratory rodents. The transfer of this concept to the clinic is aimed primarily at increasing the dose-intensity of the therapy through adjustment of drug-delivery to 24h rhythms in host tolerance. A specific technology (programmable-in-time infusion pumps) enables administration of chronotherapy to fully ambulatory patients. Phase I-III clinical trials show chronotherapy significantly increases tolerance to high doses of cancer drugs and improves antitumor activity in patients with metastatic colorectal cancer. These safe conditions of drug-delivery led to the first demonstration of the high activity of the 5-FU-leucovorin-L-OHP protocol. Chronotherapy with these three drugs also allows surgical removal of previously unresectable liver and lung metastases. This novel medico-surgical management provides hope for the cure of metastatic disease in patients with unresectable colorectal cancer metastases.

Animals↗
PubMed2002

Quality of life and chronotherapy.

The importance of evaluating patient's quality of life (QoL) in clinical practice and research is recognized clearly in oncology. In the advanced phase of disease such an evaluation represents an endpoint as important as survival. Quality of life is both a subjective and multidimensional concept evaluated mainly by validated questionnaires. In colorectal trials involving advanced stage disease the effects of different chemotherapy treatments on QoL were evaluated. Almost all the studies found no deterioration in QoL during chemotherapy. The European Organization for the Research and Treatment of Cancer (EORTC) Chronotherapy Study Group utilized three different approaches to assess QoL. The first centered on the stability of QoL during a 6mon treatment period in patients undergoing chronotherapy. The second centered on research of the biological and clinical determinants of QoL involving features of the circadian activity rhythm and patient survival and the relationship between QoL and patient performance status, response to therapy, and psychosocial variables as well as drug-induced toxicity. The third centered on the clinical effectiveness of psychological intervention on patients undergoing chronotherapy to improve psychosocial status during treatment. This papers reviews the results of EORTC Chronotherapy Group studies on QoL.

Antineoplastic Agents↗
PubMed2002

[Advantages of capoten chronotherapy of patients with hypertension in an outpatient setting].

AIM: To compare the efficiency of a short course of preventive chronotherapy and traditional therapy with capoten in an outpatient setting. MATERIAL AND METHODS: Forty-two patients with stage II essential hypertension were divided into 2 groups: 20 controls were treated with capoten in a dose of 12.5-50 mg 3 times a day and 22 received capoten once a day in the same single dose 1.5-2 h before arterial pressure (AP) acrophase. Central hemodynamics was studied by echocardiography, regional hemodynamics by reheoencephalography before and at the end of therapy. RESULTS: In the control group AP normalized after capoten therapy in 3 patients, decreased by at least 10% but did not normalize in 9, and did not change in 8 patients. The results in the chronotherapy group were as follows: AP normalized in 5, decreased by at least 15% in 13, and did not change in 4 patients. Normalization of daily profiles of hemodynamic values and more favorable shifts in the cerebral bloodflow were more often seen in patients who received chronotherapy. CONCLUSION: Capoten chronotherapy of patients with essential hypertension, carried out in an outpatient setting, is obviously preferable to traditional treatment: no side effects were observed and a better hypotensive effect was attained with lower total dose.

Adult↗
PubMed2003

[Efficacy of circadian chronotherapy via hepatic arterial infusion].

For hepatectomy after neoadjuvant chemotherapy (NAC), we applied circadian chronotherapy via the hepatic artery for multiple bilobar liver metastases from colorectal cancer. Four patients underwent chronotherapy and 16 patients underwent flat infusion therapy (5 day q 2 weeks, 4 or more courses). We used 2 drugs, (5-fluorouracil (5-FU) and l-leucovorin (l-LV)), and partially added cisplatin (CDDP) in the flat infusion group. The result was a higher response rate (75% vs 37.5%) and lower toxicity (0% vs 31.3%) in the chronotherapy group. Hepatectomy was performed on 12 of the 20 patients. The 5 responders to NAC showed better overall survival (p < 0.05) and lower remnant liver recurrence (p = 0.052) than the 7 non-responders. We therefore conclude that chronotherapy via the hepatic artery prior to hepatectomy may improve the survival of patients with multiple bilobar liver metastases.

Aged↗
PubMed2005

[Scientometrics and bibliometrics of chronotherapy].

In order to retrieve Chinese and foreign articles of chronotherapy, we searched Chinese databases of CBM, CMCC and foreign series databases in OVID and hence revealed and assessed the current status, research trend and level of chronotherapy in China and in foreign countries by means of scientometric and bibliometric parameters. ProCite5 software and handsearching were used to manage, check and statistically analyze the searched papers so as to find the parameters which included distributions of databases, years, authors, periodicals, subject headings, organizations and nations. 91 Chinese papers were identified which were distributed in 73 kinds of journals and in subject headings, e.g., Traditional Chinese medicine, cardiovascular diseases, neoplasms, asthma, peptic ulcer, diabetes mellitus, general review of chronotherapy, etc. 480 foreign articles were identified which mainly came from EMBASE and MEDLINE and were distributed in 285 types of journals and 35 nations and regions. There were 14 journals which recorded five or more articles. 12 researchers published more than five articles. Paul Brousse Hospital, University of Texas, University of Connecticut School of Medicine, Jichi Medical School and University of Minnesota were the core research institutes. There was no core author or core journal or core institute in China up till now. However, core authors, core journals and core research institutes had come into being in foreign countries; they were mainly from the Euro-American developed countries and had done well in chronotherapy.

Bibliometrics↗