Tumor Growth Rate Determines the Timing of Optimal Chronomodulated Treatment Schedules

In host and cancer tissues, drug metabolism and susceptibility to drugs vary in a circadian (24 h) manner. In particular, the efficacy of a cell cycle specific (CCS) cytotoxic agent is affected by the daily modulation of cell cycle activity in the target tissues. Anti-cancer chronotherapy, in which treatments are administered at a particular time each day, aims at exploiting these biological rhythms to reduce toxicity and improve efficacy of the treatment. The circadian status, which is the timing of physiological and behavioral activity relative to daily environmental cues, largely determines the best timing of treatments. However, the influence of variations in tumor kinetics has not been considered in determining appropriate treatment schedules. We used a simple model for cell populations under chronomodulated treatment to identify which biological parameters are important for the successful design of a chronotherapy strategy. We show that the duration of the phase of the cell cycle targeted by the treatment and the cell proliferation rate are crucial in determining the best times to administer CCS drugs. Thus, optimal treatment times depend not only on the circadian status of the patient but also on the cell cycle kinetics of the tumor. Then, we developed a theoretical analysis of treatment outcome (TATO) to relate the circadian status and cell cycle kinetic parameters to the treatment outcomes. We show that the best and the worst CCS drug administration schedules are those with 24 h intervals, implying that 24 h chronomodulated treatments can be ineffective or even harmful if administered at wrong circadian times. We show that for certain tumors, administration times at intervals different from 24 h may reduce these risks without compromising overall efficacy.     

Tumor-based rhythms of anticancer efficacy in experimental models

Experimental tumor models constitute a prerequisite toward chronotherapy testing in cancer patients. Studies in experimental models are required to understand the relation between tumor rhythms and antitumor treatments efficacy. In healthy tissues, cell proliferation, and differentiation processes are regulated precisely and exhibit marked circadian rhythmicity. Experimental and human tumors can retain circadian rhythms or display altered oscillations. Healthy tissues can also display rhythm modifications, possibly related to cancer stage. Cellular rhythms modulate the metabolism of cytotoxic agents and the cellular response to them; hence, they determine the chronopharmacology of anticancer drugs. Circadian rhythms in host tolerability and/or cancer chemotherapy efficacy have been demonstrated with nontoxic doses of drugs in several experimental tumor models, while in other ones a circadian-time effect was only seen within a specific dose range. The usual coupling between tolerability and efficacy rhythms of anticancer agents has resulted in significant improvement of their therapeutic index. Results of laboratory animal studies have been extrapolated to the design of clinical cancer therapy trials involving a chronobiological approach.     

The Effects of Chronomodulated Therapy with 5-Fluorouracil (5-Fu) and Folinic Acid (Fa) on the Toxicity and Quality of Life in Patients with Advanced Gastric Cancer

This study was designed to assess the tolerability of chronomodulated infusion chemotherapy, individualized by the rhythm of peripheral blood cells. Twenty patients with metastatic gastric cancer were randomized to chronotherapy or day-time arms of 5-fluorouracil (FU) (600 mg/m², 8 h inf.d1-5) and folinic acid (FA) (20 mg/m², iv, d1-5) in the first cycle and crossed-over to the other arm in the following cycles. Ten of 18 evaluable patients were assigned to chronotherapy arm and eight to day-time in the first cycle. Although there was no significant difference between two arms on enrollment, chronotherapy arm yielded an improvement of 45% of QLQ-C30 scores (p = 0.021) and the day-time arm had 11% improvement (p = 0.575). After the crossing-over, chronotherapy arm, again, had a significant improvement in QLQ-C30 scores, compared to the day-time arm (14% vs. -18%, p = 0.001, respectively). Mucositis/diarrhea was significantly higher in the day-time arm compared to chronotherapy arm (p = 0.015). In conclusion, chronomodulated infusion of 5-FU might improve the quality of life.     

Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer

Results of recent trials comparing combination chemotherapy consisting of 5-fluorouracil (5-FU), folinic acid (FOL), and oxaliplatin, given either as flat (A) or chronomodulated (B) infusion for metastatic colorectal cancer, were subjected to pharmaco-economic evaluation. The overall cost of treatment with the flat and chronomodulated protocols was equivalent. The expense of the delivery of medications with the chronotherapeutic arm (B) was greater than with the standard arm (A) because it was feasible to administer more courses (requiring more frequent doctor visits) and higher doses (high cost of medications) with containment of toxic reactions. Chrono-arm B was definitively more cost-effective than standard flat-arm A treatment since it made the outcome of treatment more effective; there was greater tumor response rate and longer time to progression with less treatment-associated toxicity. Finally, selection of the Melodie brand infusion pump to deliver the chronotherapy resulted in a further 18% reduction of overall costs and made it possible for patients to enjoy increased autonomy and improved quality of life.     

Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer

Results of recent trials comparing combination chemotherapy consisting of 5-fluorouracil (5-FU), folinic acid (FOL), and oxaliplatin, given either as flat (A) or chronomodulated (B) infusion for metastatic colorectal cancer, were subjected to pharmaco-economic evaluation. The overall cost of treatment with the flat and chronomodulated protocols was equivalent. The expense of the delivery of medications with the chronotherapeutic arm (B) was greater than with the standard arm (A) because it was feasible to administer more courses (requiring more frequent doctor visits) and higher doses (high cost of medications) with containment of toxic reactions. Chrono-arm B was definitively more cost-effective than standard flat-arm A treatment since it made the outcome of treatment more effective; there was greater tumor response rate and longer time to progression with less treatment-associated toxicity. Finally, selection of the Melodie brand infusion pump to deliver the chronotherapy resulted in a further 18% reduction of overall costs and made it possible for patients to enjoy increased autonomy and improved quality of life.     

Chronomodulated chemotherapy and irradiation: an idea whose time has come?

The chronomodulated delivery of systemic chemotherapy given with irradiation (chemoradiation) is driven by an understanding of: the chronobiology of normal tissue response to cytotoxic insult, chronopharmacology, and by technologic advances in vascular access and in the availability of portable programmable pumps. Since circadian variation exists in the proliferative activity of acute-reacting normal tissues like the gut and bone marrow, a potential therapeutic gain can be realized by the chronomodulated administration of S-phase chemotherapeutic agents at biological times when these normal tissues are in a different cell phase and thus relatively spared (chronotolerance). The reasons for this are complex and possibly include newly described time-keeping genes that may influence the cell cycle. Another important aspect of chronotolerance is based on chronopharmacologic behavior of S-phase chemotherapeutic radiation sensitizing agents, especially 5-fluorouracil (5-FU). In this review laboratory and clinical evidence is presented for using chronomodulated 5-FU or the topoisomerase-I inhibitor, camptothecin, when best tolerated biologically. Although the main body of this work has been accomplished with pure chemotherapy schedules, there is emerging clinical evidence this approach to treatment also applies to the application of chemoradiation. This knowledge has been exploited only recently in the clinic. These data should be viewed as a call for additional studies to investigate the precise timing of systemic chemotherapeutic radio sensitizers to ameliorate toxicity and maximize treatment effect, especially with newer and potentially more toxic chemoradiation programs.     

A randomized phase II trial of induction chemotherapy followed by cisplatin chronotherapy versus constant rate delivery combined with radiotherapy

Chronotherapy is no longer a novel concept in cancer treatment after approximately 20 years of development. Many clinical trials have provided strong supporting evidence that chronomodulated treatment yields better results than a traditional dosage regimen. This study aimed to evaluate the adverse reactions, effect on immune functions, and therapeutic efficacy of chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) combined with intensity-modulated radiation therapy (IMRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 148 patients with biopsy-diagnosed untreated stage III-IVb NPC were randomly assigned to undergo two cycles of chronomodulated infusion (study group) or flat intermittent infusion (control group) of DDP (100 mg/m2 on day 1, 21 days/cycle) synchronized with radical radiotherapy. Patients in the study group received chronomodulated infusion, with peak delivery of DDP at 16:00 pm. Patients in the control group received a routine constant rate of infusion. Both groups were treated with the same radiotherapy techniques. Over a median follow-up of 20 months, the study group had better outcomes for adverse effects and immune functions compared with the control group. During the phase of concurrent chemoradiotherapy, the incidence of nausea, vomiting, and oral mucositis in the study and control groups was 66.7% and 79.5% (p < 0.05), 47.9% and 71.2% (p < 0.05), and 73.9% and 87.7% (p < 0.05), respectively. There was no significant difference in 2-year overall survival, progression-free survival, and distant metastasis-free survival between the two groups (p > 0.05). Chronochemotherapy significantly reduced the incidence of adverse reactions and enhanced the tolerance for treatment without affecting survival. It is worth mentioning that reduced destruction of immune function is a novel area of exploration in chronotherapy research.     

Chronomodulated chemotherapy and irradiation: an idea whose time has come?

The chronomodulated delivery of systemic chemotherapy given with irradiation (chemoradiation) is driven by an understanding of: the chronobiology of normal tissue response to cytotoxic insult, chronopharmacology, and by technologic advances in vascular access and in the availability of portable programmable pumps. Since circadian variation exists in the proliferative activity of acute-reacting normal tissues like the gut and bone marrow, a potential therapeutic gain can be realized by the chronomodulated administration of S-phase chemotherapeutic agents at biological times when these normal tissues are in a different cell phase and thus relatively spared (chronotolerance). The reasons for this are complex and possibly include newly described time-keeping genes that may influence the cell cycle. Another important aspect of chronotolerance is based on chronopharmacologic behavior of S-phase chemotherapeutic radiation sensitizing agents, especially 5-fluorouracil (5-FU). In this review laboratory and clinical evidence is presented for using chronomodulated 5-FU or the topoisomerase-I inhibitor, camptothecin, when best tolerated biologically. Although the main body of this work has been accomplished with pure chemotherapy schedules, there is emerging clinical evidence this approach to treatment also applies to the application of chemoradiation. This knowledge has been exploited only recently in the clinic. These data should be viewed as a call for additional studies to investigate the precise timing of systemic chemotherapeutic radio sensitizers to ameliorate toxicity and maximize treatment effect, especially with newer and potentially more toxic chemoradiation programs.     

Somatostatin analogues in the treatment of breast and prostate cancer

Newly developed somatostatin analogues may be useful agents in the treatment of breast and prostate cancer. Potential mechanisms of antitumor action include suppression of circulating levels of trophic hormones and growth factors as well as direct effects at the tumor level, potentially involving autocrine/paracrine mechanisms. Pilot clinical trials conducted in heavily pretreated women with advanced breast cancer indicate that SMS 201–995 (Sandostatin®) has minimal toxicity and moderately suppresses stimulated growth hormone secretion and basal somatomedin-C level. Somatostatin analogues have also been found to retard the growth of experimental prostate cancer, particularly when used in combination with LHRH analogues. The therapeutic efficacy of these compounds used alone or in combination with other agents in the treatment of breast and prostate cancer remains to be established in larger clinical trials involving less heavily pretreated patients.     

Effects of Nocturnal Shiftwork on Mood States of Student Nurses

Daily mood changes were monitored over successive 24-h periods using the Profile of Mood States (POMS) (3) to assess the effect of nocturnal shiftwork on mood. Twenty-three student nurses, age range 19-24 years, were studied throughout their first experience of nocturnal shiftwork. The POMS was administered over four complete solar days during a 12-week period that included an 8-week block of night work. Five POMS dimensions displayed circadian rhythmicity. vigor-activity; fatigue-inertia; confusion-bewilderment; friendliness; and total-mood-disturbance. These five dimensions were sensitive to changes in living patterns, showing phase shifts in their circadian rhythms when subjects alternated between diurnal and nocturnal living patterns. The dimensions were also observed to be sensitive to adjustment to two different nocturnal shiftwork schedules. The subjects who worked “four on, three off showed similar phase shifts to the subjects who worked “eight on, seven off,” suggesting that mood adjustment takes place by the fourth night of a rotation of nights. The “commitment” of the students to the nocturnal living pattern was thought to have a bearing on the adaptation of the students to the nocturnal shifts, as regards mood.     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

Thoracic surface temperature rhythms as circadian biomarkers for cancer chronotherapy

The disruption of the temperature circadian rhythm has been associated with cancer progression, while its amplification resulted in cancer inhibition in experimental tumor models. The current study investigated the relevance of skin surface temperature rhythms as biomarkers of the Circadian Timing System (CTS) in order to optimize chronotherapy timing in individual cancer patients. Baseline skin surface temperature at four sites and wrist accelerations were measured every minute for 4?days in 16 patients with metastatic gastro-intestinal cancer before chronotherapy administration. Temperature and rest-activity were recorded, respectively, with wireless skin surface temperature patches (Respironics, Phillips) and an actigraph (Ambulatory Monitoring). Both variables were further monitored in 10 of these patients during and after a 4-day course of a fixed chronotherapy protocol. Collected at baseline, during and after therapy longitudinal data sets were processed using Fast Fourier Transform Cosinor and Linear Discriminant Analyses methods. A circadian rhythm was statistically validated with a period of 24?h (p?<?0.05) for 49/61 temperature time series (80.3%), and 15/16 rest-activity patterns (93.7%) at baseline. However, individual circadian amplitudes varied from 0.04?°C to 2.86?°C for skin surface temperature (median, 0.72?°C), and from 16.6 to 146.1?acc/min for rest-activity (median, 88.9?acc/min). Thirty-nine pairs of baseline temperature and rest-activity time series (75%) were correlated (r?>?|0.7|; p?<?0.05). Individual circadian acrophases at baseline were scattered from 15:18 to 6:05 for skin surface temperature, and from 12:19 to 15:18 for rest-activity, with respective median values of 01:10 (25–75% quartiles, 22:35–3:07) and 14:12 (13:14–14:31). The circadian patterns in skin surface temperature and rest-activity persisted or were amplified during and after fixed chronotherapy delivery for 5/10 patients. In contrast, transient or sustained disruption of these biomarkers was found for the five other patients, as indicated by the lack of any statistically significant dominant period in the circadian range. No consistent correlation (r?<?|0.7|, p?≥?0.05) was found between paired rest-activity and temperature time series during fixed chronotherapy delivery. In conclusion, large inter-patient differences in circadian amplitudes and acrophases of skin surface temperature were demonstrated for the first time in cancer patients, despite rather similar rest-activity acrophases. The patient-dependent coupling between both CTS biomarkers, and its possible alteration on a fixed chronotherapy protocol, support the concept of personalized cancer chronotherapy.     

Chronomodulated chemotherapy: clinical value and possibilities for dissemination in the United States

Modern medicine has been relatively slow to apply chronotherapeutic principles to standard oncologic practice. Despite the impressive body of evidence supporting the use of chronochemotherapy, with only a rare exception most oncology clinics in the United States lack the expertise and capability to implement it. At the same time, American medicine has increasingly come to recognize the importance of toxicity mitigation, cytoprotection, and quality of life for patients undergoing cancer treatment. However, toxicity mitigation strategies such as chronomodulated infusional chemotherapy and novel cytoprotective agents are not widely embraced by U.S. physicians. This article explores some reasons why this situation exists, including the influence of non-medical biases that may affect management decisions on the application of chemotherapy. The author conducted a survey of U.S. companies representing the three private insurance payers available (HMO, PPO, Indemnity) as well as representatives of Medicare and Medicaid. Responses to the survey confirmed that U.S. insurers do not at present officially reimburse for chronotherapy; however, changes will come about through educational efforts aimed at increasing awareness among insurers as to the clinical benefits and cost-effectiveness of this mode of treatment. At this juncture, the outlook for cancer chronotherapy as a first-line approach to the treatment of metastatic cancer in the United States remains uncertain. Under the current method of insurance reimbursement, the advancement of chronotherapy in the United States is threatened despite evidence that such treatment is both therapeutically sound and cost-effective.     

Chronobiological concepts underlying the chronotherapy of human lung cancer

This article reviews the experimental and clinical data that form the basis for the chronotherapy of lung carcinoma, specifically, nonsmall cell lung cancer (NSCLC). Circadian rhythms in cell kinetics, immunological and endocrinological endpoints, and tumor markers are reviewed. Chronopharmacology and chronotolerance studies on laboratory animals and clinical observations on cancer patients involving the main drugs active in lung carcinoma have prompted prospective Phase I-III studies to evaluate the application of chronobiologic concepts in the treatment of NSCLC. Circadian rhythmicity in host tolerance (chronotolerance) to medications has been confirmed in two prospective randomized lung cancer trials; a large phase II study has established the value of chronobiologic concepts to improve the therapeutic index of advanced NSCLC.     

Chronobiological concepts underlying the chronotherapy of human lung cancer

This article reviews the experimental and clinical data that form the basis for the chronotherapy of lung carcinoma, specifically, nonsmall cell lung cancer (NSCLC). Circadian rhythms in cell kinetics, immunological and endocrinological endpoints, and tumor markers are reviewed. Chronopharmacology and chronotolerance studies on laboratory animals and clinical observations on cancer patients involving the main drugs active in lung carcinoma have prompted prospective Phase I–III studies to evaluate the application of chronobiologic concepts in the treatment of NSCLC. Circadian rhythmicity in host tolerance (chronotolerance) to medications has been confirmed in two prospective randomized lung cancer trials; a large phase II study has established the value of chronobiologic concepts to improve the therapeutic index of advanced NSCLC.     

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.     

Chronopharmacology and Chronotherapeutics: Definitions and Concepts

Most knowledge of medications has been derived from single- and multiple-dose investigations in which pharmacokinetic and pharmacodynamic phenomena have been evaluated following one, usually, daytime drug administration. Chronopharmacologic studies involving the evaluation of such phenomena after each of several different clock-hour treatments during the day- and nighttime reveal that biological rhythmic processes, such as those of 24 hr, can profoundly affect the kinetics and effects of various medications. Several new concepts have arisen based on findings from chronopharmacologic investigations, such as chronokinetics, chronesthesy and chronergy. These are defined and discussed herein using illustrative examples. A major goal of chronopharmacologic research is to devise chronotherapeutic interventions. Chronotherapeutics is the optimization of drug effects and/or minimization of toxicity by timing medications with regard to biological rhythms. Chronotherapeutics takes into account predictable administration-time-dependent variation in the pharmacokinetics of drugs as well as the susceptibility of target tissues due to temporal organization of physiochemical processes and functions of the body as circadian and other rhythms. The unequally divided and once-daily theophylline treatment schedules for the clinical management of nocturnal asthma, which are discussed in this issue, represent steps toward a chronotherapy.     

Chronomodulated chemotherapy: clinical value and possibilities for dissemination in the United States

Modern medicine has been relatively slow to apply chronotherapeutic principles to standard oncologic practice. Despite the impressive body of evidence supporting the use of chronochemotherapy, with only a rare exception most oncology clinics in the United States lack the expertise and capability to implement it. At the same time, American medicine has increasingly come to recognize the importance of toxicity mitigation, cytoprotection, and quality of life for patients undergoing cancer treatment. However, toxicity mitigation strategies such as chronomodulated infusional chemotherapy and novel cytoprotective agents are not widely embraced by U.S. physicians. This article explores some reasons why this situation exists, including the influence of non-medical biases that may affect management decisions on the application of chemotherapy. The author conducted a survey of U.S. companies representing the three private insurance payers available (HMO, PPO, Indemnity) as well as representatives of Medicare and Medicaid. Responses to the survey confirmed that U.S. insurers do not at present officially reimburse for chronotherapy; however, changes will come about through educational efforts aimed at increasing awareness among insurers as to the clinical benefits and cost-effectiveness of this mode of treatment. At this juncture, the outlook for cancer chronotherapy as a first-line approach to the treatment of metastatic cancer in the United States remains uncertain. Under the current method of insurance reimbursement, the advancement of chronotherapy in the United States is threatened despite evidence that such treatment is both therapeutically sound and cost-effective.     

Clinical use of aromatase inhibitors in the treatment of advanced breast cancer

The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour growth. After failure of tamoxifen — the standard “first-line” hormonotherapy for advanced breast cancer (ABC) — the most frequently prescribed endocrine therapies are progestins and aromatase inhibitors (AIs) (“second-line” hormonotherapy). Estrogen deprivation through AIs provides effective treatment of hormone-dependent ABC in postmenopausal (PMP) women. Over the past few years, the goals of our research programme were to develop more potent, more selective and better tolerated AIs than our first AI, aminoglutethimide (AG). Lentaron® (4-hydroxyandrostenedione, formestane), a highly selective steroidal compound was the first of the new AIs to be used in clinical trials. It is a substrate analogue, administered as an i.m. injection every 2 weeks. It is effective in the treatment of ABC with an objective response rate (ORR) similar to tamoxifen and megestrol acetate (MA) and is generally well tolerated; rare instances of injection site reactions have been reported. Afema® (fadrozole HCl), a non-steroidal AI is active orally, and effectively suppresses estrogen levels in PMP women, but it is not completely selective for aromatase when administered at higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day it has an anti-tumour efficacy similar to MA, a good tolerability and no clinically relevant effects on other hormones of the endocrine system. Letrozole is the fourth of our AIs in clinical development. It is a non-steroidal, achiral, orally active, potent and highly selective competitive AI. Clinical endocrine studies have shown that the dose of 0.5 mg a day is the lowest dose achieving maximum estrogen suppression. Over a wide dose range, a lack of clinically relevant effects on other hormones of the endocrine system has confirmed its high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who failed previous therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase IIb/III study has been completed and two others are ongoing, comparing two doses of letrozole with MA or AG to confirm the anti-tumour efficacy of letrozole in the treatment of ABC in PMP women after treatment with anti-estrogens. Preliminary results from the completed trial show that letrozole 2.5 mg is superior to 0.5 mg in terms of ORR, time to progression and time to treatment failure, and is superior to the standard dose of MA in terms of ORR and tolerability. Therefore letrozole 2.5 mg can be recommended as a first choice for the treatment of PMP patients with hormone receptor-positive or unknown ABC after anti-estrogen therapy.     

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.